Kelong Han1, Jin Y Jin1, Mathilde Marchand2, Stephen Eppler1, Nicholas Choong3, Stephen P Hack3, Nalin Tikoo4, Rene Bruno2, Mark Dresser1, Luna Musib1, Nageshwar R Budha5. 1. Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA. 2. Pharsight Consulting Services, Pharsight, a Certara™ Company, Marseille, France. 3. Product Development Oncology, Genentech Inc, South San Francisco, CA, USA. 4. Statistical Programming Analysis, Genentech Inc, South San Francisco, CA, USA. 5. Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA. budha.nageshwar@gene.com.
Abstract
PURPOSE: To characterize cobimetinib pharmacokinetics and evaluate impact of clinically relevant covariates on cobimetinib pharmacokinetics. METHODS: Plasma samples (N = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in three clinical studies (MEK4592g, NO25395, GO28141). Cobimetinib was administered orally, once daily on either a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as single agent or in combination with vemurafenib. Cobimetinib doses ranged from 2.1 to 125 mg. NONMEM was used for pharmacokinetic analysis. RESULTS: A linear two-compartment model with first-order absorption, lag time and first-order elimination described cobimetinib pharmacokinetics. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V2/F) and terminal half-life were 322 L/day (58 %), 511 L (49 %) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability was estimated at 46 %. CL/F decreased with age. V2/F increased with body weight (BWT). However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib. CONCLUSION: A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.
PURPOSE: To characterize cobimetinib pharmacokinetics and evaluate impact of clinically relevant covariates on cobimetinib pharmacokinetics. METHODS: Plasma samples (N = 4886) were collected from 487 patients with various solid tumors (mainly melanoma) in three clinical studies (MEK4592g, NO25395, GO28141). Cobimetinib was administered orally, once daily on either a 21-day-on/7-day-off, 14-day-on/14-day-off or 28-day-on schedule in a 28-day dosing cycle as single agent or in combination with vemurafenib. Cobimetinib doses ranged from 2.1 to 125 mg. NONMEM was used for pharmacokinetic analysis. RESULTS: A linear two-compartment model with first-order absorption, lag time and first-order elimination described cobimetinib pharmacokinetics. The typical estimates (inter-individual variability) of apparent clearance (CL/F), central volume of distribution (V2/F) and terminal half-life were 322 L/day (58 %), 511 L (49 %) and 2.2 days, respectively. Inter-occasion variability on relative bioavailability was estimated at 46 %. CL/F decreased with age. V2/F increased with body weight (BWT). However, the impact of age and BWT on cobimetinib steady-state exposure (peak and trough concentrations and AUC following the recommended daily dose of 60 mg 21-day-on/7-day-off) was limited (<25 % changes across the distribution of age and BWT). No significant difference in cobimetinib pharmacokinetics or steady-state exposure was observed between patient subgroups based on sex, renal function, ECOG score, hepatic function tests, race, region, cancer type, and co-administration of moderate and weak CYP3A inducers or inhibitors and vemurafenib. CONCLUSION: A population pharmacokinetic model was developed for cobimetinib in cancerpatients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.
Authors: Nageshwar R Budha; Tao Ji; Luna Musib; Steve Eppler; Mark Dresser; Yuan Chen; Jin Y Jin Journal: Clin Pharmacokinet Date: 2016-11 Impact factor: 6.447
Authors: Anna Mueller-Schoell; Stefanie L Groenland; Oliver Scherf-Clavel; Madelé van Dyk; Wilhelm Huisinga; Robin Michelet; Ulrich Jaehde; Neeltje Steeghs; Alwin D R Huitema; Charlotte Kloft Journal: Eur J Clin Pharmacol Date: 2020-11-09 Impact factor: 2.953