A Study of the Effects of Posaconazole on Alectinib (RO5424802) Pharmacokinetics in Healthy Volunteers

An Open-Label, Three-Period, Fixed Sequence Study to Investigate the Effect of Multiple Oral Doses of Posaconazole, a Potent Cytochrome P450 3A Inhibitor, on the Single Dose Pharmacokinetics of RO5424802 in Healthy Subjects

This open-label study will investigate whether multiple oral doses of posaconazole affect the single dose pharmacokinetics of alectinib in healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: Alectinib; Drug: Posaconazole

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body mass index (BMI) between 18 to 32 kilogram per square meter (kg/m^2)
• Male volunteers must use effective contraception as outlined in the protocol
• Willingness to abstain from alcohol and xanthine-containing beverages or food (coffee, tea, cola, chocolate and "energy drinks") from 72 hours prior to the first dose until discharged
• Willingness to avoid prolonged sun exposure and guard against sunburn during study and follow-up

Exclusion Criteria:

• Clinically significant medical history or findings in physical examination, vital signs, or laboratory test results prior to study start
• Positive screening tests for hepatitis B or C, human immunodeficiency virus (HIV), alcohol, drugs of abuse, or tobacco
• Women of childbearing potential, or males with pregnant or lactating partners
• Regular smoking within 6 months prior to first dosing. Participants should avoid smoky environments for at least 1 week prior to each cotinine screen
• Excessive alcohol consumption
• Use of any metabolic inducers (including herbals such as St. John's Wort) within 4 weeks or 5 half-lives (whichever is longer) before the first dose of study medication, including but not limited to: rifampin, rifabutin, glucocorticoids, carbamazepine, phenytoin and phenobarbital
• Strenuous activity, sunbathing, or contact sports are not allowed from 4 days prior to entry into the clinical site until study follow-up
• Participation in an investigational drug or device study within 45 days (or 6 months for biologic therapies) prior to first dosing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort A; There will be 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 14), and Period 3 (Days 15 to 18). Alectinib will be administered as a 40 milligrams (mg) single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants). On Days 8 to 14 (Period 2) and Days 15 to 18 (Period 3) posaconazole will be administered as a 400-mg twice daily (BID) oral dose after a high-fat meal. The follow-up assessments will occur within 10 to 14 days after the last dose of posaconazole.	Drug: Alectinib; Alectinib will be administered as a single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants).; Other Names: RO5424802; Drug: Posaconazole; Posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal on Days 8 to 14 (Period 2) and Days 15 to 18 or 21 (Period 3).
EXPERIMENTAL: Cohort B; There will be 3 dosing periods in the study: Period 1 (Days 1 to 7), Period 2 (Days 8 to 14), and Period 3 (Days 15 to 21). Alectinib will be administered as a single oral dose at the dose selected based on Cohort A data on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants). On Days 8 to 14 (Period 2) and Days 15 to 21 (Period 3) posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal. The follow-up assessments will occur within 10 to 14 days after the last dose of posaconazole.	Drug: Alectinib; Alectinib will be administered as a single oral dose on Day 1 (Period 1) and Day 15 (Period 3) with an identical standardized meal (identical meal on Day 1 and Day 15 across all participants).; Other Names: RO5424802; Drug: Posaconazole; Posaconazole will be administered as a 400-mg BID oral dose after a high-fat meal on Days 8 to 14 (Period 2) and Days 15 to 18 or 21 (Period 3).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Alectinib: Cohort A		Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Cohort A	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Cmax of Alectinib: Cohort B		Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
AUClast of Alectinib: Cohort B	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of RO5424802: Cohort B	AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf).	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of RO5468924: Cohort A	RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
AUClast of RO5468924: Cohort A	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
AUC0-inf of RO5468924: Cohort A	AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Cmax of RO5468924: Cohort B	RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
AUClast of RO5468924: Cohort B	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
AUC0-inf of RO5468924: Cohort B	AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Cohort A		Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Tmax of Alectinib: Cohort B		Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Tmax of RO5468924: Cohort A	RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Tmax of RO5468924: Cohort B	RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
Metabolite/Parent Ratio for AUC0-inf: Cohort B	AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of Alectinib. The ratio is molecular weight adjusted.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
Metabolite/Parent Ratio for Cmax: Cohort B	RO5468924 is M4 metabolite of Alectinib. The ratio is molecular weight adjusted.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
Terminal Half-life (t1/2) of Alectinib: Cohort A	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
t1/2 of Alectinib: Cohort B	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing
t1/2 of RO5468924: Cohort A	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
t1/2 of RO5468924: Cohort B	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of Alectinib.	Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period, and additional samples were collected in Period 3 at 120, 144, 168, 192, and 216 hours after dosing

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (ACTUAL): March 1, 2014
• Study Completion (ACTUAL): March 1, 2014

Study Registration Dates

• First Submitted: November 7, 2013
• First Submitted That Met QC Criteria: November 7, 2013
• First Posted (ESTIMATE): November 14, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): October 11, 2016
• Last Update Submitted That Met QC Criteria: August 16, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: NP28990