A Study to Evaluate the Pharmacokinetics and Safety of Cobimetinib in Volunteers With and Without Liver Damage

Study Overview
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Brief Summary
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This study is an open-label, multi-center, single-dose, parallel group study to determine the pharmacokinetics, safety, and tolerability of cobimetinib administered at 10 mg to fasted male and female adult subjects with varying degrees of hepatic function. The study will be conducted based on the Child-Pugh classification of hepatic impairment. The anticipated duration of the study is 7.5 weeks. The target sample sizes are: 18 volunteers with varying degrees of hepatic function and up to 12 healthy control volunteers.

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Drug: cobimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between 18 and 74 years of age, inclusive Body weight >/=45 kg and body mass index between 17 and 41 kg/m2, inclusive Subjects with hepatic impairment must have a Child-Pugh score of 5 to 6 (mild), 7 to 9 (moderate), or 10 to 15 (severe) and have stable hepatic insufficiency within 1 month prior to Screening and a stable medication regimen for at least 1 month prior to Check-in Agreement to use highly effective contraceptive methods as defined in the protocol Exclusion Criteria: Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for subjects with hepatic impairment who due to their liver disease may be affected by significant medical problems which require frequent hospitalizations. Invasive systemic fungal infections need to be fully treated prior to study entry Significant history or clinical manifestations of any cardiac event that would put the subject at risk in the opinion of the Investigator Use of drugs of abuse within 1 month of Screening or during the entire study Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in this clinical study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Normal function<br> | Drug: cobimetinib<br>* single oral 10-mg dose of cobimetinib<br>|
| Experimental: Cohort 2: Mild Hepatic Impairment<br> | Drug: cobimetinib<br>* single oral 10-mg dose of cobimetinib<br>|
| Experimental: Cohort 3: Moderate Hepatic Impairment<br> | Drug: cobimetinib<br>* single oral 10-mg dose of cobimetinib<br>|
| Experimental: Cohort 4: Severe Hepatic Impairment<br> | Drug: cobimetinib<br>* single oral 10-mg dose of cobimetinib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose (0 hours [hrs]), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | AUC (0-t) was defined as area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | AUC (0 - ∞) was defined as AUC from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t- ∞). | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | AUC% extrapolated was defined as the percentage of AUC [0-∞] obtained by forward extrapolation. It is calculated as [AUC (0-∞) minus AUC(0-t]*100/ AUC (0-∞), where AUC [0-∞] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUC(0-t) is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Apparent Terminal Elimination Rate Constant (λZ) | λZ was defined as the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration of cobimetinib to decrease by one half. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Apparent Oral Clearance (CL/F) | 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. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose | 
| Apparent Volume of Distribution (Vz/F) | Volume of distribution was 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. Vz/F after the oral dose is influenced by the fraction absorbed. | Pre-dose (0 hrs), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 264, 336, 456, and 576 hrs post-dose |