An Absolute Bioavailability Study in Healthy Participants Comparing Oral to Intravenous Administration of GDC-0973 (Cobimetinib)

Phase 1

Completed

Conditions: Healthy Volunteers

Interventions: Drug: GDC-0973 IV Infusion
Drug: GDC-0973 Oral Capsules

Registration Number: NCT01249118

Lead Sponsor: Genentech, Inc.

Brief Summary: The primary objective of Part 1 of this study is to evaluate the safety and tolerability of the intravenous (IV) dose of GDC-0973. The primary objectives of Part 2 of this study are to evaluate the absolute bioavailability of GDC-0973 and to evaluate the pharmacokinetic (PK) of GDC-0973 following IV and oral administration. The secondary objective of Part 2 of this study is to evaluate the safety of GDC-0973 administered orally and intravenously.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Part 1: GDC-0973 IV Infusion First, Then GDC-0973 Capsules	GDC-0973 IV Infusion	Participants will receive single dose of GDC-0973 2 milligrams (mg) IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Part 1: GDC-0973 IV Infusion First, Then GDC-0973 Capsules	GDC-0973 Oral Capsules	Participants will receive single dose of GDC-0973 2 milligrams (mg) IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Part 2: GDC-0973 IV Infusion First, Then GDC-0973 Capsules	GDC-0973 IV Infusion	Participants will receive single dose of GDC-0973 2 mg IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Part 2: GDC-0973 IV Infusion First, Then GDC-0973 Capsules	GDC-0973 Oral Capsules	Participants will receive single dose of GDC-0973 2 mg IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period. The washout period between each period will be a minimum of 10 days.
Part 2: GDC-0973 Capsules First, Then GDC-0973 IV Infusion	GDC-0973 IV Infusion	Participants will receive single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in first intervention period followed by single dose of GDC-0973 2 mg IV infusion in second intervention period. The washout period between each period will be a minimum of 10 days.
Part 2: GDC-0973 Capsules First, Then GDC-0973 IV Infusion	GDC-0973 Oral Capsules	Participants will receive single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in first intervention period followed by single dose of GDC-0973 2 mg IV infusion in second intervention period. The washout period between each period will be a minimum of 10 days.

Primary Outcome Measures

Name	Time	Method
Volume of Distribution at Steady State (Vss) of IV GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1	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 blood concentration of a drug. Vss is the apparent volume of distribution at steady-state.
Renal Clearance (CLR) of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine	CLR was calculated as Aeu divided by AUC (0 - ∞), where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose and AUC(0 - ∞) was area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity hrs post-dose.
Mean Absorption Time (MAT)	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	MAT is mean time required for the drug to reach the central compartment. MAT was estimated from the mean resident time (MRT) from oral and IV administration. MAT was calculated as MRT last of oral dose minus MRT last of IV dose. MAT is analyzed when drug is administered orally (only for non-IV routes of administration).
Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973	Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1	The cumulative amount of drug excreted in urine over the entire collection interval of 96 hrs was calculated by adding the Aeu of the intervals 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 hrs where Aeu was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.
Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973	Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose	% Excreted is the mean percentage of dose recovery in urine and calculated as: (Aeu divided by dose) multiplied by 100, where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose.
Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973	Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	Cmax(dn) is Cmax divided by dose.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).
Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t). AUC (0-t)dn is AUC (0-t) divided by dose.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞)dn is AUC(0 - ∞) divided by dose.
Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	t1/2 is the time measured for the plasma concentration of GDC-0973 to decrease by one half.
Systemic Clearance (CL) of IV GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Apparent Oral Clearance (CL/F) of Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	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 PK modelling. 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) of Oral GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	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. Vz/F is influenced by the fraction absorbed.
Absolute Oral Bioavailability (F) of GDC-0973	Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1	Absolute oral bioavailability is the amount of drug from a formulation that reaches the systemic circulation relative to an IV dose. F = \[AUC (0-∞), oral multiplied by Dose IV\] divided by \[AUC (0-∞), IV multiplied by Dose oral\]. Absolute oral bioavailability is determined for drugs which are administered orally. IV dose is 100% in systemic circulation (dosed directly) and hence no estimation is required.