A Study of the Effect of Multiple Doses of Rifampin on the Single Dose Pharmacokinetics of RO5424802

Phase 1

Completed

• Conditions: Healthy Volunteer
• Interventions: Drug: RO5424802; Drug: rifampin

• Registration Number: NCT01940510
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-09-09
• Study First Submitted QC: 2013-09-09
• Study First Posted: 2013-09-12
• Study Start: 2013-10
• Primary Completion: 2013-10
• Study Completion: 2013-10
• Results First Submitted: 2016-08-25
• Results First Submitted QC: 2016-08-25
• Results First Posted: 2016-10-18
• Status Verified: 2016-11
• Last Update Submitted: 2016-11-01
• Last Update Posted: 2016-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Healthy male and female volunteers, 18 to 55 years of age inclusive. Healthy status will be defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, and a complete physical examination
• Body mass index (BMI) between 18 to 32 kg/m2 inclusive
• Nonsmoking subjects and former smoking subjects (who have not smoked for the past six months before first dosing)
• Female subjects must be surgically sterile or postmenopausal for the past year
• Male subjects and their partners of childbearing potential must be willing to use two effective methods of contraception, one of which must be a barrier method (e.g., condom) during the study and for 90 days after the last drug administration

Exclusion Criteria

• Women of childbearing potential, pregnant or lactating women, or males with female partners who are pregnant or lactating
• Positive urine test for drugs of abuse, alcohol, or cotinine test at screening or prior to admission to the study unit
• Suspicion of regular consumption of drug(s) of abuse including marijuana
• Current smokers or subjects who have discontinued smoking less than six months prior to first dosing
• History (within three months of Screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption will be prohibited 72 hours prior to entry in the clinical site center and throughout the entire study (including the washout period) until discharge
• Positive for hepatitis B, hepatitis C, or HIV infection
• Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever time period is longer) or 6 months for biologic therapies prior to first dosing
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, absorption, distribution, metabolism or excretion of study medication, or that would, in the opinion of the PI, pose an unacceptable risk to the subject in this study
• History of hypersensitivity to any of the additives in the RO5424802 formulation (lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, sodium lauryl sulphate, magnesium stearate)
• Any history of hypersensitivity to or contraindication to the use of rifampin or other rifamycins or history of severe drug-related allergic reactions or hepatoxicity

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Healthy subjects	RO5424802	-
Healthy subjects	rifampin	-

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) 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	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).
Maximum Observed Plasma Concentration (Cmax) 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	Cmax is the maximum observed alectinib plasma concentration, presented in nanogram per milliliter (ng/mL).

Secondary Outcome Measures

Name	Time	Method
Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for Cmax	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	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.
Cmax of RO5468924	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	Cmax is the maximum observed RO5468924 (the major pharmacologically active metabolite of alectinib) plasma concentration, presented in ng/mL.
Apparent Oral Clearance (CL/F) 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	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.
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib and RO5468924	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	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.
Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924	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 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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib and RO5468924	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	The Tmax is the time from alectinib administration to reach Cmax for alectinib and RO5468924 (the major pharmacologically active metabolite of alectinib).
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)	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	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).
AUC(0-inf) of RO5468924	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	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.
Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)	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	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.
Apparent Volume of Distribution (Vz/F) 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	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.
Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax	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	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).