Healthy Participants
Conditions
Brief summary
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.
Interventions
DRUGCobimetinib
10 milligram (mg) (2\* 5 mg capsules) will be administered orally on Day 1 of Period 1 and Day 4 of Period 2
DRUGItraconazole
200 mg oral solution will be administered once daily from Day 1 to Day 14 of Period 2
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole | 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 | Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole | 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 is the time measured for the plasma concentration to decrease by one half. |
| Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole | 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 | 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. |
| Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole | 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 | 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. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole | 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 | Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach. |
| Tmax of Itraconazole and Hydroxy-Itraconazole | 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 | Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. |
| Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole | Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4 | 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. |
| Cmax of Itraconazole and Hydroxy-Itraconazole | 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 | Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cobimetinib + Itraconazole Cobimetinib 10 mg administered orally on Day 1 of Period 1 and Day 4 of Period 2. Each period duration was 14 days. Itraconazole 200 mg oral solution was administered once daily from Day 1 to Day 14 of Period 2. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2 | Non-Compliance | 1 |
Baseline characteristics
| Characteristic | Cobimetinib + Itraconazole |
|---|---|
| Age, Continuous | 38 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 16 |
| serious Total, serious adverse events | 0 / 16 |
Outcome results
Primary
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.
Time frame: 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
Population: PK population. Number of Participants Analyzed indicates participants evaluable for this outcome measure and n signifies participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole | Period 1: Cobimetinib Alone (n=14) | 241 ng*hr/mL | Geometric Coefficient of Variation 51.5 |
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole (n=12) | 1596 ng*hr/mL | Geometric Coefficient of Variation 23 |
Comparison: Only participants with PK parameter data from both Period 1 Day 1 and Period 2 Day 4 (n=11) were included for statistical analyses.90% CI: [563.7, 801.9]
Primary
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.
Time frame: 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
Population: Pharmacokinetic (PK) population consisted of all participants who received at least 1 dose of cobimetinib and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole | Period 1: Cobimetinib Alone | 5.21 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 38.1 |
| Cobimetinib + Itraconazole | Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole | 16.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 27.7 |
Comparison: Ratio of Least squares (LS) means (Cobimetinib with Itraconazole/Cobimetinib alone) of natural log-transformed parameter (expressed as a percent).90% CI: [268.1, 374]
Secondary
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.
Time frame: 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
Population: PK population. Number of Participants Analyzed indicates participants evaluable for this outcome measure and n signifies participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole | Period1: Cobimetinib Alone (n=14) | 41.4 liter per hour (L/hr) | Geometric Coefficient of Variation 51.5 |
| Cobimetinib + Itraconazole | Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole (n=12) | 6.27 liter per hour (L/hr) | Geometric Coefficient of Variation 23 |
Secondary
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.
Time frame: 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
Population: PK population. Number of Participants Analyzed indicates participants evaluable for this outcome measure and n signifies participants evaluable for specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole | Period1: Cobimetinib Alone (n=14) | 3233 liter (L) | Geometric Coefficient of Variation 27.5 |
| Cobimetinib + Itraconazole | Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole (n=12) | 1065 liter (L) | Geometric Coefficient of Variation 36.1 |
Secondary
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.
Time frame: Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole | Itraconazole | 15607 ng*hr/mL | Geometric Coefficient of Variation 26.8 |
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole | Hydroxy-Itraconazole | 23176 ng*hr/mL | Geometric Coefficient of Variation 23.2 |
Secondary
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.
Time frame: 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
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole | Period 1: Cobimetinib Alone | 209 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 49.4 |
| Cobimetinib + Itraconazole | Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole | 1220 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 24 |
90% CI: [488.2, 698.2]
Secondary
Cmax of Itraconazole and Hydroxy-Itraconazole
Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.
Time frame: 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
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cobimetinib + Itraconazole | Cmax of Itraconazole and Hydroxy-Itraconazole | Itraconazole | 1480 ng/mL | Geometric Coefficient of Variation 42.6 |
| Cobimetinib + Itraconazole | Cmax of Itraconazole and Hydroxy-Itraconazole | Hydroxy-Itraconazole | 1243 ng/mL | Geometric Coefficient of Variation 26.4 |
Secondary
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.
Time frame: 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
Population: PK population. Number of Participants Analyzed indicates participants evaluable for this outcome measure and n signifies participants evaluable for specified category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Itraconazole | Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole | Period1: Cobimetinib Alone (n=14) | 58.6 hours |
| Cobimetinib + Itraconazole | Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole (n=12) | 118 hours |
Secondary
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.
Time frame: 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
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Itraconazole | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole | Period1: Cobimetinib Alone | 2.00 hours |
| Cobimetinib + Itraconazole | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole | Period 2: Cobimetinib With Itraconazole | 4.00 hours |
Secondary
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.
Time frame: 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
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cobimetinib + Itraconazole | Tmax of Itraconazole and Hydroxy-Itraconazole | Itraconazole | 2.00 hours |
| Cobimetinib + Itraconazole | Tmax of Itraconazole and Hydroxy-Itraconazole | Hydroxy-Itraconazole | 4.00 hours |