title: Absolute bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on cobimetinib absorption in healthy subjects.
abstract: Cobimetinib is a potent and highly selective inhibitor of MEK1/2. Since cobimetinib exhibited absorption variability in cancer patients, a series of single-dose studies in healthy subjects were conducted to determine absolute bioavailability and elucidate potential effects of formulation, food, and elevated gastric pH on cobimetinib bioavailability. Three crossover trials were performed with a 20 mg cobimetinib oral dose: absolute bioavailability using a 2 mg intravenous infusion (n = 13), relative bioavailability of tablets versus capsules and food effect (n = 20), and drug interaction with a proton pump inhibitor (20 mg of rabeprazole daily for 5 days prior to cobimetinib administration; n = 20). Absolute bioavailability of cobimetinib was 46.2% (24.2, CV %), likely due to metabolism rather than incomplete absorption. The mean systemic clearance of cobimetinib was low (11.7 L/h [28.2, CV %]). Administration of cobimetinib tablets with a high-fat meal delayed drug absorption (prolonged tmax) but had no statistically significant effect on cobimetinib exposure (Cmax and AUC0-∞). Tablet and capsule formulations of cobimetinib showed comparable exposures. Cobimetinib exhibited delayed absorption (tmax) in the presence of rabeprazole, with no statistically significant effects on drug exposure (Cmax and AUC0-∞) in the fasted state. In conclusion, cobimetinib oral absorption was not affected by change in formulation, food, or elevated gastric pH.
authors.affiliation: Genentech, Inc. , 1 DNA Way, South San Francisco, California, 94080, United States.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.forename: Steve
authors.initials: S
authors.lastname: Eppler
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rooney
authors.forename: Iris T
authors.initials: IT
authors.lastname: Chan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
mesh_terms: D000042:Absorption / Q000187:drug effects; D000284:Administration, Oral; D000328:Adult; D001384:Azetidines / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D005502:Food; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010880:Piperidines / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D064750:Rabeprazole / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001384:Azetidines; D010880:Piperidines; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; C574276:cobimetinib