A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants

A Phase 1, Open-Label Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Subjects

This open-label, 2-period, fixed sequence, drug interaction study will investigate the effect of co-administration of itraconazole on the pharmacokinetics of cobimetinib in healthy participants. Participants will receive multiple repeating doses of cobimetinib and itraconazole.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: Cobimetinib; Drug: Itraconazole

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75247

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:

• Healthy adult participants
• Within body mass index (BMI) range 18.5 to 32 kilogram per meter square (kg/m^2), inclusive
• Creatine phosphokinase levels below 2.5 times the upper limit of normal (ULN) and if elevated, not clinically significant
• Liver function tests for aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase below 2 times the ULN; bilirubin below 1.5 times the ULN; and all liver function test elevations not clinically significant
• In good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), and vital signs
• Clinical laboratory evaluations within the reference range for the test laboratory, unless deemed not clinically significant by the Investigator
• Negative test for selected drugs of abuse at screening and at each check-in
• Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and anti-hepatitis C virus [HCV]) and negative human immunodeficiency virus (HIV) antibody screens
• Females non-pregnant or non-lactating
• Males and females (of child-bearing potential) to use two forms of adequate contraception

Exclusion Criteria:

• Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs; except that appendectomy, hernia repair, and/or cholecystectomy will be allowed
• History of diabetes mellitus and/or elevated fasting glucose at baseline
• History or presence of an abnormal ECG, which in the Investigator's opinion, is clinically significant
• History of alcoholism or drug addiction within 1 year prior to study start
• Use of any tobacco- or nicotine-containing products (within 6 months prior to study start and during the entire study
• Participation in any other investigational study or biologic agent trial in which receipt of an investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, or exposure to any biological therapy or investigational biological agent within 90 days prior to study entry and during the entire study from study start to study completion, inclusive

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cobimetinib + Itraconazole	Drug: Cobimetinib; 10 milligram (mg) (2* 5 mg capsules) will be administered orally on Day 1 of Period 1 and Day 4 of Period 2; Other Names: GDC-0973; Drug: Itraconazole; 200 mg oral solution will be administered once daily from Day 1 to Day 14 of Period 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole	Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole	AUC (0 - inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf) of cobimetinib with and without itraconazole, assessed using a model independent approach.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole	Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole	AUC (0-t) = Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (0-t) of cobimetinib with and without itraconazole was assessed. It was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations using a model independent approach.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole	Plasma half-life is the time measured for the plasma concentration to decrease by one half.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole	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. Clearance was estimated using a model independent approach.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole	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.	Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Cmax of Itraconazole and Hydroxy-Itraconazole	Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.	Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Tmax of Itraconazole and Hydroxy-Itraconazole	Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.	Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4
Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole	AUC (0-24) = Area under the plasma concentration versus time curve from time zero (predose) to 24 hours postdose (0-24) of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.	Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 22, 2013
• First Submitted That Met QC Criteria: August 22, 2013
• First Posted (Estimate): August 28, 2013

Study Record Updates

• Last Update Posted (Estimate): August 4, 2016
• Last Update Submitted That Met QC Criteria: June 22, 2016
• Last Verified: June 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 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: GP28620