title: Population pharmacokinetics and dosing implications for cobimetinib in patients with solid tumors.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Marseille, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Marchand
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Eppler
authors.affiliation: Product Development Oncology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Choong
authors.affiliation: Product Development Oncology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
authors.affiliation: Statistical Programming Analysis, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Nalin
authors.initials: N
authors.lastname: Tikoo
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara™ Company, Marseille, France.
authors.forename: Rene
authors.initials: R
authors.lastname: Bruno
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Dresser
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.affiliation: Clinical Pharmacology, Genentech Inc, South San Francisco, CA, USA. budha.nageshwar@gene.com.
authors.forename: Nageshwar R
authors.initials: NR
authors.lastname: Budha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D007211:Indoles; D009363:Neoplasm Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C574276:cobimetinib
keywords: Cancer; Cobimetinib; NONMEM; Pharmacokinetics