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The purpose of this study is to determine the effects of belatacept on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm: Inje Cocktail + Belatacept | Experimental | Inje Cocktail consisting of (200 mg Caffeine, 50 mg losartan tablet, 40 mg Omeprazole capsule, 30 mg Dextromethorphan capsule and 5 mg Midazolam oral syrup) administered on Days 1, 4, 7 and 11 Belatacept 10 mg/kg Intravenous (IV) solution, administered on Day 4 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Caffeine | Drug |
| ||
| Losartan |
| Measure | Description | Time Frame |
|---|---|---|
| Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11 |
| Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population |
| Measure | Description | Time Frame |
|---|---|---|
| Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bristol-Myers Squibb | Bristol-Myers Squibb | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Healthcare Discoveries, Llc D/B/A Icon Development Solutions | San Antonio | Texas | 78209 | United States |
45 were enrolled and 22 dosed with study drug. Reasons for not dosing: 5 withdrew consent, 1 lost to follow up, 1 poor/non-compliance, 15 no longer met study criteria, and 1 other.
Study initiated January 2013 and completed April 2013. Participants (healthy volunteers) checked into a clinical pharmacology unit (CPU) on Day -1 for screening.
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| ID | Title | Description |
|---|---|---|
| FG000 | Inje Cocktail Alone and Inje Cocktail Plus Belatacept | Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All participants who received study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Inje Cocktail Alone and Inje Cocktail Plus Belatacept | Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Adjusted Geometric Mean Maximum Drug Concentration (Cmax) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Cmax measured in nanograms per milliliter (ng/mL). Inje cocktail components (Midazolam) measured using High Performance Liquid Chromatography (HPLC) with Tandem Mass Spectrometry (MS/MS) Detection. | Participants who received any study drug and had at least 1 adequate Pharmacokinetic (PK) profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
Day 1 to Day of discharge (Day 46 ±2 days)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Inje Cocktail Alone and Inje Cocktail Plus Belatacept | Single oral doses of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) were administered on Days 1, 4, 7 and 11. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered on Day 4. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA 16.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Bristol-Myers Squibb Study Director | Bristol-Myers Squibb | Clinical.Trials@bms.com |
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| ID | Term |
|---|---|
| D002110 | Caffeine |
| D019808 | Losartan |
| D009853 | Omeprazole |
| D003915 | Dextromethorphan |
| D008874 | Midazolam |
| D000069594 | Abatacept |
| ID | Term |
|---|---|
| D014970 | Xanthines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D011688 | Purinones |
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|
| Omeprazole | Drug |
|
| Dextromethorphan | Drug |
|
| Midazolam | Drug |
|
| Belatacept | Biological |
|
|
Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection. |
| Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population | Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population | AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng*h/mL. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h). | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h) | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration [AUC(0-T)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h). | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population | Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 1'-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1'-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants | Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study). | Day 1 to Day of discharge (Day 46±2) |
| Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants | Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. AST: >1.25*Pre-Rx if Pre-Rx >ULN or 1.25*ULN if Pre-Rx <= ULN or Pre-Rx is missing. BUN: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. Phosphorus: <0.85*LLN if Pre-RX >= LLN or is missing or if Pre-Rx < LLN. total Protein: <0.9*LLN if Pre-Rx>= LLN or is missing or Pre-Rx > LLN. Creatine Kinase: >1.5*Pre-Rx if Pre-Rx > ULN or is missing or Pre-Rx is <= ULN. Lactate Dehydrogenase: >1.25*ULN if Pre-Rx <= ULN or missing, >1.5*Pre-Rx if Pre-Rx > ULN. | Day -1 to Day 46 ±2 days or at early termination |
| Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants | Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: *10^9 cells per liter (c/L) < 0.85*Pre-Rx if Pre-Rx < LLN or <0.9*LLN if LLN <= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): *10^12 c/L < 0.85* Pre-Rx if Pre-Rx < 1.5, <1.5 if Pre-Rx >= 1.5, < 1.5 if Pre-Rx missing. Urine blood from dipstick: >=2 if Pre-Rx <1 or was missing or if Pre-Rx >=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) >= 2 if Pre-Rx <2 or if Pre-Rx was missing or >=4 if Pre-Rx >=2. | Day -1 to Day 46 ±2 days or at early termination |
| Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants | Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval >210 milliseconds (msec); QRS > 120 msec, QT > 500 msec or > 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) > 450 msec or change from baseline of > 30 msec to <= 60 msec or change from baseline > 60 msec. | Day 1 to Day 46 ±2 days or at early termination |
| Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants | Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 |
| Mean Change From Baseline in Sitting Heart Rate - All Treated Participants | Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 |
| Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days) | Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | Baseline and Day 46 ±2 days |
| Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days) | Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | Baseline and Day 46 ±2 days |
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| Body Mass Index (kg/m^2) | body mass index (BMI): weight in kilograms (kg)/[height in meters (m)]2 | Mean | Standard Deviation | kg/m^2 |
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| ID | Title | Description |
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| OG000 | Day 1 Inje Cocktail | Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 1. |
| OG001 | Day 4 Inje Cocktail Plus Belatacept | Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 4. A single 10 mg/kg intravenous (IV) infusion of belatacept over 30 minutes was administered only on Day 4. |
| OG002 | Day 7 Inje Cocktail | Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 7. |
| OG003 | Day 11 Inje Cocktail | Single oral dose of Inje Cocktail consisting of: caffeine (200 mg), losartan (50 mg tablet), omeprazole (40 mg delayed-release capsule), dextromethorphan (30 mg), and midazolam (5 mg oral syrup) was administered on Day 11. |
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| Secondary | Time of Maximum Observed Plasma Concentration (Tmax) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Tmax was measured in hours (h). | Posted | Median | Full Range | h | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Plasma Half-Life (T-HALF) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan, and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. T-HALF was measured in hours (h). | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Mean | Standard Deviation | h | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Apparent Total Body Clearance (CLT/F) of the Inje Cocktail Components (Midazolam, Losartan, Omeprazole, Dextromethorphan and Caffeine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of dextromethorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. CLT/F was measured as liters/hour (L/h) | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Cmax of Inje Cocktail Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail component metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail component metabolites were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | AUC(0-T) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration [AUC(0-T)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | AUC(INF) of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without Coadministration of Belatacept - PK Evaluable Population | Area under the plasma concentration-time curve from time zero extrapolated to infinite time [AUC(INF)] was measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Tmax of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. Time of maximum observed plasma concentration (Tmax) was measured in hours (h). | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Median | Full Range | h | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | T-HALF of Inje Cocktail Component Metabolites (1'-Hydroxy-Midazolam, E-3174, 5-Hydroxyomeprazole, Dextrorphan, and Paraxanthine) With and Without the Coadministration of Belatacept - PK Evaluable Population | Plasma half-life (T-HALF) was measured in hours (h). Samples for assessment of plasma concentrations of Inje cocktail components metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Mean | Standard Deviation | h | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of Paraxanthine AUC(0-T) to Caffeine AUC(0-T) and Paraxanthine AUC (INF) to Caffeine AUC (INF), Corrected for Molecular Weight [MR_AUC(0-T) and MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of Paraxanthine (Cmax) to Caffeine (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (paraxanthine) to parent (caffeine) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and their metabolites were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of E-3174 AUC(0-T) to Losartan AUC(0-T) and E3174 AUC (INF) to Losartan AUC (INF) Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of E-3174 (Cmax) to Losartan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (E-3174) to parent (losartan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of 5-Hydroxyomeprazole AUC(0-T) to Omeprazole AUC(0-T) and 5-Hydroxyomeprazole AUC(INF) to Omeprazole AUC(INF) , Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC(INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-Hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of 5-Hydroxyomeprazole (Cmax) to Omeprazole (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-hydroxyomeprazole) to parent (omeprazole) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of 5-Dextrorphan AUC(0-T) to Dextromethorphan AUC(0-T) and 5-Dextrorphan AUC(INF) to Dextromethorphan AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-dextrorphan ) to parent (dextromethorphan) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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| Secondary | Ratio of 5-Dextrorphan (Cmax) to Dextromethorphan (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (5-dextrorphan) to parent (dextromethorphan) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. The poor metabolizer of CYP2D6 was excluded from summary of Dextrorphan parameters. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
| Secondary | Ratio of 1'-Hydroxy-Midazolam AUC(0-T) to Midazolam AUC(0-T) and 1'-Hydroxy-Midazolam AUC(INF) to Midazolam AUC(INF), Corrected for Molecular Weight [MR_AUC(0-T), MR_AUC (INF)] With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. AUC (0-T) and AUC (INF) measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
| Primary | Adjusted Geometric Mean Area Under the Concentration Time Curve (AUC) From Zero to Last Concentration (0-T) and AUC Extrapolated to Infinity (INF) of Midazolam With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC(0-T): area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration and AUC (INF): AUC from time zero extrapolated to infinite time were measured in ng*h/mL. Samples for the assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for midazolam with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Midazolam measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean Cmax of Losartan With and Without the Coadministration of Belatacept - PK Evaluable Population | Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Losartan With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC (0-T): area under the concentration curve from time 0 to the time of the last quantifiable concentration and AUC (INF) extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for losartan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (losartan) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean Cmax of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | Cmax: Maximum observed plasma concentration was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Omeprazole With and Without the Coadministration of Belatacept - Pharmacokinetic (PK) Evaluable Population | AUC(0-T): Area under the plasma concentration-time curve from time zero zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity were measured in ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for omeprazole with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. Inje cocktail components (omeprazole) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean Cmax of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population | Cmax was measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Dextromethorphan With and Without the Coadministration of Belatacept - PK Evaluable Population | AUC(0-T): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and AUC (INF): AUC extrapolated to infinity, were measured as ng*h/mL. Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) and their metabolites (1'-hydroxy-midazolam, E-3174, 5-hydroxyomeprazole, dextrorphan, and paraxanthine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Adjusted geometric mean for dextromethorphan with and without belatacept, along with adjusted geometric mean ratios for Days 4, 7, and 11 versus Day 1, respectively, are presented. The poor metabolizer of CYP2D6 was excluded from the statistical analysis. Inje cocktail components (dextromethorphan) measured using HPLC with MS/MS Detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean Cmax of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. Cmax was measured in ng/mL. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Primary | Adjusted Geometric Mean AUC (0-T) and AUC (INF) of Caffeine With and Without the Coadministration of Belatacept - PK Evaluable Population | Samples for assessment of plasma concentrations of Inje cocktail components (midazolam, losartan, omeprazole, dextromethorphan and caffeine) were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. AUC (0-T) and AUC (INF) were measured as ng*h/mL. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | 90% Confidence Interval | ng*h/mL | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
|
|
|
|
| Secondary | Ratio of 1'-Hydroxy-Midazolam (Cmax) to Midazolam (Cmax), Corrected for Molecular Weight (MR_Cmax) With and Without Coadministration of Belatacept - PK Evaluable Population | Metabolite (1'-hydroxy-midazolam) to parent (midazolam) ratio was corrected for molecular weight. Cmax measured in ng/mL. Samples for assessment of plasma concentrations of Inje cocktail components and the metabolites of those components were collected at time = 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours relative to the dosing of belatacept on Day 4 and Inje cocktail dosing on Days 1, 4, 7, and 11, respectively. Inje cocktail components were each measured using HPLC with MS/MS detection. | Evaluable PK population: Participants who received any study drug and had at least 1 adequate PK profile for any Inje cocktail analytes (parent or metabolite). | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose to 24 hours after dose of the Inje Cocktail on Days 1, 4, 7 and 11 |
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|
| Secondary | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and AEs Leading to Discontinuation - All Treated Participants | Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Events captured from Day 1 (pre-dose) to last day prior to discharge (Day 46 ±2). In the total group, a participant with an AE is only counted once (ie, data reflected in Days 1, 4, 7, and 11 below could be the same participant with an AE on multiple days of the study). | All participants who received any study medication. | Posted | Number | participants | Day 1 to Day of discharge (Day 46±2) |
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| Secondary | Number of Participants With Marked Serum Chemistry Laboratory Abnormalities - All Treated Participants | Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46, and at early termination, after 10 hours fasting. Upper limits of normal (ULN); Lower limits of normal (LLN); Pre-therapy (Rx); micromoles per liter (µmol/L); millimoles per liter (mmol/L); grams per liter (g/L); Units per liter (U/L); Aspartate Aminotransferase (AST); Blood Urea Nitrogen (BUN) Total Bilirubin: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. AST: >1.25*Pre-Rx if Pre-Rx >ULN or 1.25*ULN if Pre-Rx <= ULN or Pre-Rx is missing. BUN: >1.1*ULN if Pre-Rx<= ULN or Pre-Rx is missing, or >1.2*Pre-Rx if Pre-Rx >ULN. Phosphorus: <0.85*LLN if Pre-RX >= LLN or is missing or if Pre-Rx < LLN. total Protein: <0.9*LLN if Pre-Rx>= LLN or is missing or Pre-Rx > LLN. Creatine Kinase: >1.5*Pre-Rx if Pre-Rx > ULN or is missing or Pre-Rx is <= ULN. Lactate Dehydrogenase: >1.25*ULN if Pre-Rx <= ULN or missing, >1.5*Pre-Rx if Pre-Rx > ULN. | Participants who received any study medication and had laboratory test results. | Posted | Number | participants | Day -1 to Day 46 ±2 days or at early termination |
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| Secondary | Number of Participants With Marked Hematology and Urinalysis Laboratory Abnormalities - All Treated Participants | Samples for laboratory tests were obtained at Screening visit, Day -1 or prior to dosing on Day 1, Days 3, 6, 10, 46 ±2, and at early termination, after 10 hours fasting. Leukocytes: *10^9 cells per liter (c/L) < 0.85*Pre-Rx if Pre-Rx < LLN or <0.9*LLN if LLN <= Pre-Rx or Pre-Rx is missing. Neutrophils (absolute): *10^12 c/L < 0.85* Pre-Rx if Pre-Rx < 1.5, <1.5 if Pre-Rx >= 1.5, < 1.5 if Pre-Rx missing. Urine blood from dipstick: >=2 if Pre-Rx <1 or was missing or if Pre-Rx >=1. Urinary microscopic white blood cells (WBC) and red blood cells (RBC) >= 2 if Pre-Rx <2 or if Pre-Rx was missing or >=4 if Pre-Rx >=2. | Participants who received any study medication and had laboratory test results. | Posted | Number | participants | Day -1 to Day 46 ±2 days or at early termination |
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| Secondary | Number of Participants With Out-of-Range Electrocardiogram Intervals - All Treated Participants | Participants had 12-Lead electrocardiograms (ECGs) performed at Screening Visit, Day 1 prior to dosing, Day 46 ±2, and at early termination. Definition of out-of-range: PR Interval >210 milliseconds (msec); QRS > 120 msec, QT > 500 msec or > 30 msec change from baseline (Day 1); QT with Fridericia correction (QTcF) > 450 msec or change from baseline of > 30 msec to <= 60 msec or change from baseline > 60 msec. | All participants who received any study medication and had an ECG performed on Day 1, Day 46 or early termination. | Posted | Number | participants | Day 1 to Day 46 ±2 days or at early termination |
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| Secondary | Mean Change From Baseline in Sitting Systolic and Diastolic Blood Pressure - All Treated Participants | Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Pressures were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | All participants who received any study medication and had a baseline and specific day blood pressure measurement available. | Posted | Mean | Standard Deviation | mm Hg | Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 |
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| Secondary | Mean Change From Baseline in Sitting Heart Rate - All Treated Participants | Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and the heart rate was measured in beats per minute (bpm). Heart Rates were obtained at screening visit, Day -1, and at 0 hour (pre-dose), 0.5 hour (post dose), and 2 hours (post dose) on Days 1, 4, 7, 11. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | All participants who received study medication and had baseline and specific day measurement. | Posted | Mean | Standard Deviation | bpm | Baseline and 0.5 and 2.0 hours Post Dose on Days 1, 4, 7, and 11 |
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| Secondary | Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Study Discharge (Day 46±2 Days) | Systolic and Diastolic blood pressures were taken after the participant had been sitting quietly for at least 5 minutes and the pressures were measured in millimeters of mercury (mm Hg). Systolic and Diastolic blood pressures were taken on Day 46 (day of discharge from the study). Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | All participants who had received study drug during the treatment period and had measurements at baseline and at discharge. | Posted | Mean | Standard Deviation | mm Hg | Baseline and Day 46 ±2 days |
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| Secondary | Mean Change From Baseline in Heart Rate at Study Discharge (Day 46±2 Days) | Heart Rate was taken after the participant had been sitting quietly for at least 5 minutes and was measured in beats per minute (bpm). Hear rate was taken on Day 46 (day of discharge) during the follow up period. Baseline was defined as last non-missing result with a collection date-time less than the date-time of the first active dose of study drug. | All participants who received study drug during the treatment period and had measurements at baseline and discharge. | Posted | Mean | Standard Deviation | bpm | Baseline and Day 46 ±2 days |
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|
|
| 0 |
| 22 |
| 3 |
| 22 |
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D013777 | Tetrazoles |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D011725 | Pyridines |
| D001562 | Benzimidazoles |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D018796 | Immunoconjugates |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D012712 | Serum Globulins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D005916 | Globulins |
| Losartan (N= 22, 21, 21, 20) |
|
| Omeprazole (N=22,21,21,20) |
|
| Dextromethorphan (N=21, 19, 19, 19) |
|
| Caffeine (N= 22,21,21,18) |
|
| Losartan (N=22, 21, 21, 20) |
|
| Omeprazole (N= 22, 19, 21, 18) |
|
| Dextromethorphan (N=18, 17, 18, 15) |
|
| Caffeine (N=22, 21, 21, 18) |
|
| Losartan (N=22, 21, 21, 20) |
|
| Omeprazole (N=22, 19, 21, 18) |
|
| Dextromethorphan (N=18,17,18,18) |
|
| Caffeine (N=22, 21, 21, 18) |
|
| E-3174 (N=22, 21, 21, 20) |
|
| 5-Hydroxyomeprazole (N=22, 21, 21, 20) |
|
| Dextrorphan (N=21,20,20,19) |
|
| Paraxanthine (N=17,19,18,18) |
|
| E-3174 (N= 22,21,21,20) |
|
| 5-hydroxyomeprazole (N=22,21,21,20) |
|
| dextrorphan (N=21,20,20,19) |
|
| paraxanthine (N=17,19,18,18) |
|
| E-3174 (N=22,20,21,20) |
|
| 5-hydroxyomeprazole (N=22,20,21,17 |
|
| dextrorphan (N=21,20,20,19) |
|
| paraxanthine (N=7,8,6,6) |
|
| E-3174 (N=22, 21, 21, 20) |
|
| 5-Hydroxyomeprazole (N=22,21,21,20) |
|
| Dextrorphan (N=21,20,20,19) |
|
| Paraxanthine (N=17, 19, 18, 18) |
|
| E-3174 (N=22, 20, 21, 20) |
|
| 5-Hydroxyomeprazole (N=22,20,21,17) |
|
| Dextrorphan (N=21,20,20,19) |
|
| Paraxanthine (N=7,8,6,6) |
|
| MR_AUC(INF) ratio; N=7, 8, 6, 6 |
|
| MR_AUC (INF) ratio; N=22,20,21,20 |
|
| MR_AUC (INF) ratio; N=22,19,21,17 |
|
| MR_AUC (INF) ratio; N=18,17,18,15 |
|
| MR_(INF) ratio; N=22, 21, 20, 20 |
|
| AUC (INF);N=22, 21, 21, 20) |
|
| Adjusted geometric mean ratio |
| 0.966 |
| 2-Sided |
| 90 |
| 0.889 |
| 1.049 |
| No |
| Superiority or Other |
| AUC (0-T) | Adjusted geometric mean ratio | 1.033 | 2-Sided | 90 | 0.950 | 1.123 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.049 | 2-Sided | 90 | 0.975 | 1.127 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 0.968 | 2-Sided | 90 | 0.892 | 1.049 | No | Superiority or Other |
| AUC(INF) | Adjusted geometric mean ratio | 1.031 | 2-Sided | 90 | 0.948 | 1.121 | No | Superiority or Other |
| Adjusted geometric mean ratio |
| 0.911 |
| 2-Sided |
| 90 |
| 0.830 |
| 1.000 |
| No |
| Superiority or Other |
| Adjusted geometric mean ratio | 0.994 | 2-Sided | 90 | 0.885 | 1.116 | No | Superiority or Other |
| AUC (INF) N=22, 21, 21, 20) |
|
| Adjusted geometric mean ratio |
| 1.016 |
| 2-Sided |
| 90 |
| 0.936 |
| 1.103 |
| No |
| Superiority or Other |
| AUC (0-T) | Adjusted geometric mean ratio | 1.001 | 2-Sided | 90 | 0.893 | 1.121 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.011 | 2-Sided | 90 | 0.942 | 1.085 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.016 | 2-Sided | 90 | 0.938 | 1.101 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.002 | 2-Sided | 90 | 0.896 | 1.121 | No | Superiority or Other |
| Adjusted geometric mean ratio |
| 1.292 |
| 2-Sided |
| 90 |
| 1.090 |
| 1.531 |
| No |
| Superiority or Other |
| Adjusted geometric mean ratio | 1.178 | 2-Sided | 90 | 0.971 | 1.429 | No | Superiority or Other |
| AUC (INF); (N= 22, 19, 21, 18) |
|
| Adjusted geometric mean ratio |
| 1.228 |
| 2-Sided |
| 90 |
| 1.092 |
| 1.381 |
| No |
| Superiority or Other |
| AUC (0-T) | Adjusted geometric mean ratio | 1.215 | 2-Sided | 90 | 1.047 | 1.410 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.193 | 2-Sided | 90 | 1.091 | 1.304 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.227 | 2-Sided | 90 | 1.093 | 1.379 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.300 | 2-Sided | 90 | 1.141 | 1.482 | No | Superiority or Other |
| Adjusted geometric mean ratio |
| 0.922 |
| 2-Sided |
| 90 |
| 0.793 |
| 1.071 |
| No |
| Superiority or Other |
| Adjusted geometric mean ratio | 0.856 | 2-Sided | 90 | 0.709 | 1.034 | No | Superiority or Other |
| AUC (INF); N= 18, 17, 18, 15 |
|
| Adjusted geometric mean ratio |
| 1.003 |
| 2-Sided |
| 90 |
| 0.856 |
| 1.175 |
| No |
| Superiority or Other |
| AUC (0-T) | Adjusted geometric mean ratio | 0.963 | 2-Sided | 90 | 0.821 | 1.130 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 0.877 | 2-Sided | 90 | 0.783 | 0.982 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.031 | 2-Sided | 90 | 0.885 | 1.200 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.022 | 2-Sided | 90 | 0.839 | 1.245 | No | Superiority or Other |
| Adjusted geometric mean ratio |
| 0.922 |
| 2-Sided |
| 90 |
| 0.857 |
| 0.993 |
| No |
| Superiority or Other |
| Adjusted geometric mean ratio | 0.954 | 2-Sided | 90 | 0.885 | 1.028 | No | Superiority or Other |
| AUC (INF); N= 22, 21, 21, 18 |
|
| Adjusted geometric mean ratio |
| 0.986 |
| 2-Sided |
| 90 |
| 0.902 |
| 1.076 |
| No |
| Superiority or Other |
| AUC (0-T) | Adjusted geometric mean ratio | 1.027 | 2-Sided | 90 | 0.942 | 1.120 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 0.939 | 2-Sided | 90 | 0.868 | 1.017 | No | Superiority or Other |
| Adjusted geometric mean ratio | 1.002 | 2-Sided | 90 | 0.914 | 1.098 | No | Superiority or Other |
| AUC (INF) | Adjusted geometric mean ratio | 1.036 | 2-Sided | 90 | 0.940 | 1.142 | No | Superiority or Other |
| SAEs |
|
| Deaths |
|
| AEs leading to discontinuation |
|
| Title | Measurements |
|---|---|
|
| Inorganic Phosphorus <0.85*LLN mmol/L (N=22) |
|
| Total Protein <0.9*LLN g/L (N=22) |
|
| Creatine Kinase > 1.5* Pre-Rx U/L (N=22) |
|
| Lactate Dehydrogenase >1.25*ULN U/L (N=22) |
|
| Title | Measurements |
|---|---|
|
| Urinary RBC microscopic >= 2 (N=8) |
|
| Urinary WBC microscopic >= 2 (N=8) |
|
| Systolic 2.0 hour post dose (N=22,21,21,20) |
|
| Diastolic 0.5 hour post dose (N=22,21,21,20) |
|
| Diastolic 2.0 hour post dose (N=22,21,21,20) |
|
| Heart Rate 2.0 hour post dose (N=22, 21, 21, 20) |
|