| Primary | Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline pharmacokinetic (PK) sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | nanograms per milliliter (ng/mL) | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| | | Title | Denominators | Categories |
|---|
| Day -7 | | | | Day 1 | | | | Day 14 | | |
| | Group IDs | Group Description | Statistical Method | Statistical Comment | P-Value | P-Value Comment | Parameter Type | Parameter Value | Dispersion Type | Dispersion Value | Confidence Interval Sides | Confidence Interval % | CI Lower Limit | CI Upper Limit | CI Lower Limit Comment | CI Upper Limit Comment | Estimate Comment | Tested Non-Inferiority | Non-Inferiority Type | Non-Inferiority Comment | Other Analysis Description |
|---|
| | | | | | Geometric LS Mean Ratio | 1.17 | | | 2-Sided | 90 | 0.978 | 1.40 | | | | | Other | | | | | | | | |
|
| Primary | Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Primary | Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Primary | Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14 | AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | nanograms*hour per milliliter (ng*hr/mL) | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Primary | AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Primary | AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Primary | AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Primary | AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | milligrams (mg) | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | mg | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | mg | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | mg | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Primary | Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Primary | Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Primary | AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Primary | AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUCinf (metabolite) × MW (parent)] / [AUCinf (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [AUClast (metabolite) × MW (parent)] / [AUClast (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 1-OH midazolam was the metabolite of midazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Paraxanthine was the metabolite of caffeine. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. Hydroxybupropion was the metabolite of bupropion. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 | MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by [Cmax (metabolite) × MW (parent)] / [Cmax (parent) × MW (metabolite)]. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 | Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Ratio | | 0 to 8 hours after dosing on Days -7, 1 and 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Secondary | AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14. | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - [predose concentration*e^(-Kel*t)], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 2 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Liters (L)/hour (h) | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | L/h | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Litre | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Litre | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of dose | | Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Fe for E-3174 on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of dose | | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Fe for Dextromethorphan on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of dose | | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Fe for Dextrorphan on Day -7, Day 1 and Day 14 | Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days -7, 1, and 14. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of dose | | 0 to 8 hours postdose on Day -7, Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Cmax of Encorafenib on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Secondary | Cmax of LHY746 on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
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| Secondary | Cmax of Binimetinib on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Secondary | Cmax of AR00426032 on Day 1 and Day 14 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUClast of Encorafenib on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUClast of LHY746 on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
|
| Secondary | AUClast of Binimetinib on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUClast of AR00426032 on Day 1 and Day 14 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. AR00426032 was the metabolite of binimetinib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
|
| Secondary | Tmax of Encorafenib on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Secondary | Tmax of LHY746 on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | Tmax of Binimetinib on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | Participants received a single oral dose of rosuvastatin tablet 10 mg and bupropion IR tablet 75 mg on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
|
| Secondary | Tmax of AR00426032 on Day 1 and Day 14 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUCinf of Encorafenib on Day 1 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUCinf of Binimetinib on Day 1 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | AUCinf of AR00426032 on Day 1 | AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number of analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
|
| Secondary | T1/2 of Encorafenib on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | T1/2 of LHY746 on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
|
| Secondary | T1/2 of Binimetinib on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
|
| Secondary | T1/2 of AR00426032 on Day 1 and Day 14 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib. | All participants in Arms 1 and 2 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 1 and 14. Number of participants analyzed represents the total number of participants in each arm in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
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| Secondary | AUC%Extrap of Encorafenib on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of LHY746 on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. LHY746 was the metabolite of encorafenib. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of Binimetinib on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | AUC%Extrap of AR00426032 on Day 1 | AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf. AR00426032 was the metabolite of binimetinib. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Percentage of AUC | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Kel of Encorafenib on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of LHY746 on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of Binimetinib on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Kel of AR00426032 on Day 1 | Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Fraction/hour | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | CL/F of Encorafenib on Day 1 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | L/h | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | CL/F of Binimetinib on Day 1 | CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14). | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | L/h | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Vz/F of Encorafenib on Day 1 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the total number of participants in Arm 1 in the evaluable PK set. Number of analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Litre | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
| |
| Secondary | Vz/F of Binimetinib on Day 1 | Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel. | All participants in Arm 1 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Day 1. Number of participants analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Litre | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1. | | | | ID | Title | Description |
|---|
| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Cmax of Binimetinib on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Cmax of AR00426032 on Day 14 and Day 21 | Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | AUClast of Binimetinib on Day 14 and Day 21 | AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
| |
| Secondary | AUClast of AR00426032 on Day 14 and Day 21 | AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Tmax of Encorafenib on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Tmax of LHY746 on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Tmax of Binimetinib on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
| |
| Secondary | Tmax of AR00426032 on Day 14 and Day 21 | Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Median | Full Range | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
| |
| Secondary | T1/2 of Encorafenib on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
| |
| Secondary | T1/2 of LHY746 on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
|---|
| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | T1/2 of Binimetinib on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | T1/2 of AR00426032 on Day 14 and Day 21 | T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib. | All participants in Arm 3 who received at least 1 dose of any study intervention and had at least 1 post-baseline PK sample with an associated bioanalytical result, and who were with sufficient concentration data to calculate at least 1 PK parameter on Days 14 and 21. Number of participants analyzed represents the total number of participants in Arm 3 in the evaluable PK set. Number analyzed represents the number of participants who had reportable parameter values. | Posted | | Geometric Mean | Geometric Coefficient of Variation | Hours | | Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 | | | | ID | Title | Description |
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| OG000 | Arm 3 - Modafinil | Participants received continuous treatment with encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) from Day 1 until treatment discontinuation criteria were met. Continuous treatment of modafinil (tablet, 400 mg QD) was started on Day 15 through Day 21. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 28 days (Day 1 to Day 28). |
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| Secondary | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. | All participants who received at least 1 dose of encorafenib/binimetinib. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail (DDI Phase) | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All drugs were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Number of Participants With Laboratory Abnormalities in the DDI Phase | Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell [RBC],platelet,white blood cell count [WBC],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. | All participants who received at least 1 dose of encorafenib/binimetinib. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase | Vital signs (temperature, pulse rate [PR]), systolic blood pressure [SBP]), and diastolic blood pressure [DBP]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP>=100 millimeters of mercury (mm Hg)/less than or equal to (<=) 50 mmHg with increase/decrease from baseline of >=15 mmHg; SBP: >=160 mmHg/<=90 mmHg with increase/decrease from baseline of >=20 mmHg; PR: >=120 beats per minute (bpm)/<=50 bpm with increase/decrease from baseline of >=15 bpm; temperature for Arms 1 and 3: >=37.5°C/<=35°C; Arms 2: >=37.5°C/<=36°C. | All participants who received at least 1 dose of encorafenib/binimetinib. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion |
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| Secondary | Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase | Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF >450 - <=480 mesc, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. QT interval >450 - <=480 msec, >480 - <=500 msec, >500 msec, increase from baseline >30 - <=60 msec and increase from baseline >60 msec. Heart rate increase from baseline >25% and value >100 bpm and decrease from baseline >25% and value <60 bpm. PR interval increase from baseline >25% and value >200 msec. QRS interval increase from baseline >25% and value >110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure. | All participants who received at least 1 dose of encorafenib/binimetinib. Here, 'Number Analyzed' signifies participants evaluable for the specified rows. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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| Secondary | Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase | LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and <-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%. | All participants who received at least 1 dose of encorafenib/binimetinib. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 mg, dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg QD) and binimetinib (tablet, 45 mg BID) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). | | OG001 | Arm 2 - Rosuvastatin and Bupropion | |
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| Secondary | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE. | All participants who received at least 1 dose of encorafenib/binimetinib. | Posted | | Number | | Count of Participants | | After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase | | | | ID | Title | Description |
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| OG000 | Arm 1 - CYP Probe Cocktail | Participants received a single oral dose of the CYP probe cocktail (losartan tablet 25 milligrams [mg], dextromethorphan capsule 30 mg, caffeine liquid 50 mg, omeprazole capsule 20 mg, and midazolam syrup 2 mg) on Day -7, Day 1, and Day 14. Encorafenib (capsule, 450 mg once daily [QD]) and binimetinib (tablet, 45 mg twice daily [BID]) were continuously administered initiated on Day 1 until treatment discontinuation criteria were met. All study interventions were taken within 10 minutes. There were 2 treatment phases, a DDI phase followed by a post-DDI phase. The duration of the DDI phase was 35 days (Day -7 to Day 28). |
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