Healthy Volunteers
Conditions
Brief summary
This study will be an open-label, randomized, 3-way, 6-sequence crossover study in healthy participants for determining the relative bioavailability of the tablet formulation to the capsule formulation and the effect of food on the relative bioavailability of the tablet formulation.
Interventions
DRUGCobimetinib
Cobimetinib 20 mg will be given orally as tablet formulation in fasted or fed state, or as capsule formulation in fasted state.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Within body mass index range 18.5 to 29.9 kilograms per meter square (kg/m\^2) * 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 * Negative test for selected drugs of abuse at Screening and at each Check-in * Negative hepatitis panel and anti-hepatitis C virus and negative human immunodeficiency virus (HIV) antibody screens * Healthy males and females of non-child-bearing potential or who agree to use effective contraception
Exclusion criteria
* Significant history or clinical manifestation of any significant 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 * 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 cholecystectomy will be allowed * History or presence of an abnormal ECG * History of alcoholism or drug addiction prior to study start * Use of any tobacco-containing or nicotine-containing products prior to study start * Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 28 days or 5 half-lives, whichever is longer, prior to study start * Use of any prescription medications/products, including proton pump inhibitors, within 14 days prior to study start * Poor peripheral venous access * Any acute or chronic condition that would limit the participant's ability to complete and/or participate in this clinical study * Female participant is pregnant, lactating, or breastfeeding * Predisposing factors to retinal vein occlusion (RVO)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | AUCinf = 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). |
| Maximum Observed Plasma Concentration (Cmax) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | — |
| Minimum Observed Plasma Concentration (Cmin) | Day 1 at 0 hour (predose) | — |
| Apparent Oral Clearance (CL/F) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | 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 from population pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Volume of Distribution (V/F) | Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose | 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 absorbed. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population All participants randomized to any treatment. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout Period of 10 Days | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 36 years |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 19 | 9 / 19 | 8 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 20 |
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. Clearance was estimated from population pharmacokinetic modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib One 20 mg Tablet [Fasted] | Apparent Oral Clearance (CL/F) | 25.6 Liters per hour (L/hr) | Geometric Coefficient of Variation 34.7 |
| Cobimetinib Four 5 mg Capsules [Fasted] | Apparent Oral Clearance (CL/F) | 25.2 Liters per hour (L/hr) | Geometric Coefficient of Variation 45.1 |
| Cobimetinib One 20 mg Tablet [Fed] | Apparent Oral Clearance (CL/F) | 23.3 Liters per hour (L/hr) | Geometric Coefficient of Variation 42.4 |
Primary
Apparent Volume of Distribution (V/F)
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 absorbed.
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib One 20 mg Tablet [Fasted] | Apparent Volume of Distribution (V/F) | 2103 Liters (L) | Geometric Coefficient of Variation 40.4 |
| Cobimetinib Four 5 mg Capsules [Fasted] | Apparent Volume of Distribution (V/F) | 1930 Liters (L) | Geometric Coefficient of Variation 50.2 |
| Cobimetinib One 20 mg Tablet [Fed] | Apparent Volume of Distribution (V/F) | 1900 Liters (L) | Geometric Coefficient of Variation 38.3 |
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf)
AUCinf = 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).
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib One 20 mg Tablet [Fasted] | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | 780 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 34.7 |
| Cobimetinib Four 5 mg Capsules [Fasted] | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | 717 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 45.1 |
| Cobimetinib One 20 mg Tablet [Fed] | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) | 858 nanograms*hours/milliliter (ng*hr/mL) | Geometric Coefficient of Variation 42.4 |
90% CI: [83.9, 107]
90% CI: [98.2, 124]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1 at 0 hour (predose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 hours postdose
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib One 20 mg Tablet [Fasted] | Maximum Observed Plasma Concentration (Cmax) | 16.0 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.5 |
| Cobimetinib Four 5 mg Capsules [Fasted] | Maximum Observed Plasma Concentration (Cmax) | 14.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45.9 |
| Cobimetinib One 20 mg Tablet [Fed] | Maximum Observed Plasma Concentration (Cmax) | 17.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43.1 |
90% CI: [84.2, 111]
90% CI: [93.8, 123]
Primary
Minimum Observed Plasma Concentration (Cmin)
Time frame: Day 1 at 0 hour (predose)
Population: Pharmacokinetic parameters populations included all enrolled participants. Here, number of participants analyzed = participants who were evaluable for this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cobimetinib One 20 mg Tablet [Fasted] | Minimum Observed Plasma Concentration (Cmin) | 0.307 ng/mL | Geometric Coefficient of Variation 46.6 |
| Cobimetinib Four 5 mg Capsules [Fasted] | Minimum Observed Plasma Concentration (Cmin) | 0.36 ng/mL | Geometric Coefficient of Variation 56.6 |
| Cobimetinib One 20 mg Tablet [Fed] | Minimum Observed Plasma Concentration (Cmin) | 0.361 ng/mL | Geometric Coefficient of Variation 60.3 |