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This single center, open-label, 3-period, fixed-sequence study will evaluate the effect of multiple oral doses of rifampin on the pharmacokinetics of a single oral dose of RO5424802 in healthy volunteers. Subjects will receive a single dose of RO5424802 on Days 1 and 17 and rifampin daily from Days 8 to Day 20.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Healthy subjects | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| RO5424802 | Drug | Single dose without (Day 1) and with (Day 17) co-administration of rifampin |
|
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (*) hour per milliliter (ng*hour/mL). | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Maximum Observed Plasma Concentration (Cmax) of Alectinib | Cmax is the maximum observed alectinib plasma concentration, presented in nanogram per milliliter (ng/mL). | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Measure | Description | Time Frame |
|---|---|---|
| AUC(0-inf) of RO5468924 | AUC(0-inf) is the area under the RO5468924 (the major pharmacologically active metabolite of alectinib) plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the drug over time. AUC(0-inf) is presented in ng*hour/mL. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Clinical Trials | Hoffmann-La Roche | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Austin | Texas | 78744 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Whole Study: Alectinib + Rifampin | There were 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 16), and Period 3 (Days 17 to 21). Participants following an overnight fast of at least 10 hours ate a standard meal in 30 minutes or less and 30 minutes after start of the meal received alectinib (RO5424802) 600 milligram (mg) capsules (four 150 mg capsules) orally alone on Day 1 (Period 1), with rifampin (600 mg capsules [two 300 mg capsules] orally) on Day 17 (Period 3), and rifampin alone was administered from Days 8 through 16 (Period 2) and from Days 18 through 20 (Period 3). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety analysis set included all participants who received at least one dose of the study treatment and had at least 1 postdose safety assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Whole Study: Alectinib + Rifampin | There were 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 16), and Period 3 (Days 17 to 21). Participants following an overnight fast of at least 10 hours ate a standard meal in 30 minutes or less and 30 minutes after start of the meal received alectinib 600 mg capsules orally alone on Day 1 (Period 1), with rifampin (600 mg capsules orally) on Day 17 (Period 3), and rifampin alone was administered from Days 8 through 16 (Period 2) and from Days 18 through 20 (Period 3). |
| 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 | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (*) hour per milliliter (ng*hour/mL). | The Pharmacokinetic (PK) analysis set included all participants who received both scheduled doses of alectinib (on Day 1 and Day 17), and provided adequate PK assessments. | Posted | Mean | Standard Deviation | ng*hour/mL | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
Day 1 through follow-up (up to 31 days)
Safety analysis set. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A treatment-emergent AE (TEAE) was defined as an AE that began or worsened in severity on or after the first dose of the study drug.
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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 | Treatment Period 1: Alectinib | Participants following an overnight fast of at least 10 hours ate a standard meal in 30 minutes or less and 30 minutes after start of the meal received alectinib 600 mg capsules orally on Day 1 of treatment period 1. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Chromaturia | Renal and urinary disorders | MedDRA (16.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Communications | Hoffmann-La Roche | 800-821-8590 | genentech@druginfo.com |
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| ID | Term |
|---|---|
| C582670 | alectinib |
| D012293 | Rifampin |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| rifampin | Drug | Multiple doses Days 8-16 and Days 17-20 |
|
| Cmax of RO5468924 | Cmax is the maximum observed RO5468924 (the major pharmacologically active metabolite of alectinib) plasma concentration, presented in ng/mL. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for Cmax | Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib and RO5468924 | AUC(0-last) is the area under the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) plasma concentration time-curve from time zero to the last measured concentration. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng*hour/mL. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib and RO5468924 | The Tmax is the time from alectinib administration to reach Cmax for alectinib and RO5468924 (the major pharmacologically active metabolite of alectinib). | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Apparent Oral Clearance (CL/F) of Alectinib | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Apparent Volume of Distribution (Vz/F) of Alectinib | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed. | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the molar plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (*) hour per liter (nmol*hour/L). | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L). | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
| years |
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| Gender | Count of Participants | Participants |
|
| OG001 | Treatment Period 3: Alectinib + Rifampin | Participants following an overnight fast of at least 10 hours ate a standard meal in 30 minutes or less and 30 minutes after start of the meal received alectinib 600 mg capsules orally on Day 1 of treatment period 3 (Day 17). Participants following an overnight fast of at least 10 hours received rifampin 600 mg capsules orally once daily from Day 18 through 20. On Day 17, rifampin was coadministered with alectinib, 30 minutes after start of the standard meal. |
|
|
|
| Primary | Maximum Observed Plasma Concentration (Cmax) of Alectinib | Cmax is the maximum observed alectinib plasma concentration, presented in nanogram per milliliter (ng/mL). | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
|
| Secondary | AUC(0-inf) of RO5468924 | AUC(0-inf) is the area under the RO5468924 (the major pharmacologically active metabolite of alectinib) plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the drug over time. AUC(0-inf) is presented in ng*hour/mL. | PK analysis set | Posted | Mean | Standard Deviation | ng*hour/mL | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
|
| Secondary | Cmax of RO5468924 | Cmax is the maximum observed RO5468924 (the major pharmacologically active metabolite of alectinib) plasma concentration, presented in ng/mL. | PK analysis set | Posted | Mean | Standard Deviation | ng/mL | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
|
| Secondary | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented. | PK analysis set | Posted | Geometric Mean | Standard Deviation | ratio | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
| Secondary | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for Cmax | Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented. | PK analysis set | Posted | Geometric Mean | Standard Deviation | ratio | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
| Secondary | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib and RO5468924 | AUC(0-last) is the area under the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) plasma concentration time-curve from time zero to the last measured concentration. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng*hour/mL. | PK analysis set | Posted | Mean | Standard Deviation | ng*hour/mL | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib and RO5468924 | The Tmax is the time from alectinib administration to reach Cmax for alectinib and RO5468924 (the major pharmacologically active metabolite of alectinib). | PK analysis set | Posted | Median | Full Range | hours | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
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| Secondary | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib. | PK analysis set | Posted | Mean | Standard Deviation | hours | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
|
| Secondary | Apparent Oral Clearance (CL/F) of Alectinib | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | PK analysis set | Posted | Mean | Standard Deviation | liters/hour | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
|
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| Secondary | Apparent Volume of Distribution (Vz/F) of Alectinib | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed. | PK analysis set | Posted | Mean | Standard Deviation | liters | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
|
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| Secondary | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the molar plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (*) hour per liter (nmol*hour/L). | PK analysis set | Posted | Mean | Standard Deviation | nmol*hour/L | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
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| Secondary | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L). | PK analysis set | Posted | Mean | Standard Deviation | nmol/L | Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib-dose in each intervention period |
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|
| 0 |
| 24 |
| 1 |
| 24 |
| EG001 | Treatment Period 2: Rifampin | Participants following an overnight fast of at least 10 hours received rifampin 600 mg capsules orally once daily from Day 8 through 16. | 0 | 24 | 16 | 24 |
| EG002 | Treatment Period 3: Alectinib + Rifampin | Participants following an overnight fast of at least 10 hours ate a standard meal in 30 minutes or less and 30 minutes after start of the meal received alectinib 600 mg capsules orally on Day 1 of treatment period 3 (Day 17). Participants following an overnight fast of at least 10 hours received rifampin 600 mg capsules orally once daily from Day 18 through 20. On Day 17, rifampin was coadministered with alectinib, 30 minutes after start of the standard meal. | 0 | 24 | 1 | 24 |
| Faeces discoloured | Gastrointestinal disorders | MedDRA (16.1) | Non-systematic Assessment |
|
| Infrequent bowel movements | Gastrointestinal disorders | MedDRA (16.1) | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (16.1) | Non-systematic Assessment |
|
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |