Healthy Volunteer
Conditions
Brief summary
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.
Interventions
DRUGcobimetinib
single oral 10-mg dose of cobimetinib
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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)] | 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 | 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). |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 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 | 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- ∞). |
| Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 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 | 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. |
| Apparent Terminal Elimination Rate Constant (λZ) | 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 | λZ was defined as the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase. |
| Plasma Decay Half-Life (t1/2) | 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 is the time measured for the plasma concentration of cobimetinib to decrease by one half. |
| Apparent Oral Clearance (CL/F) | 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 | 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. |
| Apparent Volume of Distribution (Vz/F) | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Normal Hepatic Function Participants with normal hepatic function received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 10 |
| Cohort 2: Mild Hepatic Impairment Participants with mild hepatic impairment (Child-Pugh Class A, score of 5 to 6, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 6 |
| Cohort 3: Moderate Hepatic Impairment Participants with moderate hepatic impairment (Child-Pugh Class B, score of 7 to 9, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 6 |
| Cohort 4: Severe Hepatic Impairment Participants with severe hepatic impairment (Child-Pugh Class c, score of 10 to 15, inclusive) received single oral dose of 10 mg cobimetinib (two 5 mg capsules) on Day 1 of study. | 6 |
| Total | 28 |
Baseline characteristics
| Characteristic | Cohort 1: Normal Hepatic Function | Cohort 2: Mild Hepatic Impairment | Cohort 3: Moderate Hepatic Impairment | Cohort 4: Severe Hepatic Impairment | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56 Years STANDARD_DEVIATION 6.8 | 59 Years STANDARD_DEVIATION 2.8 | 61 Years STANDARD_DEVIATION 2.9 | 53 Years STANDARD_DEVIATION 5.3 | 57 Years STANDARD_DEVIATION 5.6 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 5 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 10 | 3 / 6 | 2 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
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.
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Apparent Oral Clearance (CL/F) | 23.4 Liter per hr (L/hr) | Standard Deviation 11.6 |
| Cohort 2: Mild Hepatic Impairment | Apparent Oral Clearance (CL/F) | 22.9 Liter per hr (L/hr) | Standard Deviation 13.2 |
| Cohort 3: Moderate Hepatic Impairment | Apparent Oral Clearance (CL/F) | 21.9 Liter per hr (L/hr) | Standard Deviation 11.7 |
| Cohort 4: Severe Hepatic Impairment | Apparent Oral Clearance (CL/F) | 31.7 Liter per hr (L/hr) | Standard Deviation 14.5 |
Primary
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.
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Apparent Terminal Elimination Rate Constant (λZ) | 0.00942 1 per hr (1/hr) | Standard Deviation 0.00259 |
| Cohort 2: Mild Hepatic Impairment | Apparent Terminal Elimination Rate Constant (λZ) | 0.00852 1 per hr (1/hr) | Standard Deviation 0.00315 |
| Cohort 3: Moderate Hepatic Impairment | Apparent Terminal Elimination Rate Constant (λZ) | 0.00702 1 per hr (1/hr) | Standard Deviation 0.00181 |
| Cohort 4: Severe Hepatic Impairment | Apparent Terminal Elimination Rate Constant (λZ) | 0.00509 1 per hr (1/hr) | Standard Deviation 0.00114 |
Primary
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.
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Apparent Volume of Distribution (Vz/F) | 2580 Liter | Standard Deviation 1300 |
| Cohort 2: Mild Hepatic Impairment | Apparent Volume of Distribution (Vz/F) | 2880 Liter | Standard Deviation 1370 |
| Cohort 3: Moderate Hepatic Impairment | Apparent Volume of Distribution (Vz/F) | 3230 Liter | Standard Deviation 1650 |
| Cohort 4: Severe Hepatic Impairment | Apparent Volume of Distribution (Vz/F) | 6280 Liter | Standard Deviation 2480 |
Primary
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- ∞).
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 637 ng*hr/mL | Standard Deviation 606 |
| Cohort 2: Mild Hepatic Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 530 ng*hr/mL | Standard Deviation 206 |
| Cohort 3: Moderate Hepatic Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 579 ng*hr/mL | Standard Deviation 301 |
| Cohort 4: Severe Hepatic Impairment | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | 370 ng*hr/mL | Standard Deviation 163 |
Comparison: AUC (0 - ∞) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and mild hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [59.3, 160.6]
Comparison: AUC (0 - ∞) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and moderate hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [62.6, 169.6]
Comparison: AUC (0 - ∞) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and severe hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [40.4, 116.2]
Primary
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).
Time frame: 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
Population: PK Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | 604 ng*hr/mL | Standard Deviation 606 |
| Cohort 2: Mild Hepatic Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | 498 ng*hr/mL | Standard Deviation 200 |
| Cohort 3: Moderate Hepatic Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | 539 ng*hr/mL | Standard Deviation 296 |
| Cohort 4: Severe Hepatic Impairment | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] | 268 ng*hr/mL | Standard Deviation 181 |
Comparison: AUC (0-t) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and mild hepatic impairment (test) where, hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [52, 186]
Comparison: AUC (0-t) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and moderate hepatic impairment (test) where, hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [54, 193.2]
Comparison: AUC (0-t) was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and severe hepatic impairment (test) where, hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [22.5, 80.5]
Primary
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.
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 7.37 % extrapolated | Standard Deviation 4.37 |
| Cohort 2: Mild Hepatic Impairment | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 6.69 % extrapolated | Standard Deviation 2.63 |
| Cohort 3: Moderate Hepatic Impairment | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 8.17 % extrapolated | Standard Deviation 4.36 |
| Cohort 4: Severe Hepatic Impairment | Extrapolated Area Under the Curve (AUC Percent [%] Extrapolated) | 15.90 % extrapolated | Standard Deviation 4.79 |
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 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
Population: Pharmacokinetic (PK) population included all participants who received at least one dose of cobimetinib and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Maximum Observed Plasma Concentration (Cmax) | 10.7 nanograms per milliliter (ng/mL) | Standard Deviation 7.41 |
| Cohort 2: Mild Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) | 9.00 nanograms per milliliter (ng/mL) | Standard Deviation 4.09 |
| Cohort 3: Moderate Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) | 8.03 nanograms per milliliter (ng/mL) | Standard Deviation 2.49 |
| Cohort 4: Severe Hepatic Impairment | Maximum Observed Plasma Concentration (Cmax) | 3.97 nanograms per milliliter (ng/mL) | Standard Deviation 1.77 |
Comparison: Cmax was analyzed using a mixed model analysis of variance (ANOVA) to determine 90% confidence interval (CI) of the ratio between normal hepatic function (reference) and mild hepatic impairment (test) where hepatic impairment group was a fixed factor. The least squares (LS) means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [59.2, 143.4]
Comparison: Cmax was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and moderate hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [54.6, 132.1]
Comparison: Cmax was analyzed using a mixed model ANOVA to determine 90% CI of the ratio between normal hepatic function (reference) and severe hepatic impairment (test) where hepatic impairment group was a fixed factor. The LS means of the test and reference treatments obtained from the mixed model were back-transformed to give geometric LS means (a point estimate).90% CI: [25.1, 60.7]
Primary
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.
Time frame: 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
Population: PK population. Here, number of participants analyzed signified those participants who were evaluable for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Normal Hepatic Function | Plasma Decay Half-Life (t1/2) | 79.1 hr | Standard Deviation 22.7 |
| Cohort 2: Mild Hepatic Impairment | Plasma Decay Half-Life (t1/2) | 95.2 hr | Standard Deviation 48.2 |
| Cohort 3: Moderate Hepatic Impairment | Plasma Decay Half-Life (t1/2) | 104.0 hr | Standard Deviation 24.4 |
| Cohort 4: Severe Hepatic Impairment | Plasma Decay Half-Life (t1/2) | 143.0 hr | Standard Deviation 40.4 |
Primary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 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
Population: PK population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Normal Hepatic Function | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2 hrs |
| Cohort 2: Mild Hepatic Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 6 hrs |
| Cohort 3: Moderate Hepatic Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4 hrs |
| Cohort 4: Severe Hepatic Impairment | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 2 hrs |