title: Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans.
abstract: The pharmacokinetics, metabolism, and excretion of cobimetinib, a MEK inhibitor, were characterized in healthy male subjects (n = 6) following a single 20 mg (200 μCi) oral dose. Unchanged cobimetinib and M16 (glycine conjugate of hydrolyzed cobimetinib) were the major circulating species, accounting for 20.5% and 18.3% of the drug-related material in plasma up to 48 hours postdose, respectively. Other circulating metabolites were minor, accounting for less than 10% of drug-related material in plasma. The total recovery of the administered radioactivity was 94.3% (±1.6%, S.D.) with 76.5% (±2.3%) in feces and 17.8% (±2.5%) in urine. Metabolite profiling indicated that cobimetinib had been extensively metabolized with only 1.6% and 6.6% of the dose remaining as unchanged drug in urine and feces, respectively. In vitro phenotyping experiments indicated that CYP3A4 was predominantly responsible for metabolizing cobimetinib. From this study, we concluded that cobimetinib had been well absorbed (fraction absorbed, Fa = 0.88). Given this good absorption and the previously determined low hepatic clearance, the systemic exposures were lower than expected (bioavailability, F = 0.28). We hypothesized that intestinal metabolism had strongly attenuated the oral bioavailability of cobimetinib. Supporting this hypothesis, the fraction escaping gut wall elimination (Fg) was estimated to be 0.37 based on F and Fa from this study and the fraction escaping hepatic elimination (Fh) from the absolute bioavailability study (F = Fa × Fh × Fg). Physiologically based pharmacokinetics modeling also showed that intestinal clearance had to be included to adequately describe the oral profile. These collective data suggested that cobimetinib was well absorbed following oral administration and extensively metabolized with intestinal first-pass metabolism contributing to its disposition.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California takahashi.ryan@gene.com.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Takahashi
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rooney
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Mary
authors.initials: M
authors.lastname: Gates
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: S Cyrus
authors.initials: SC
authors.lastname: Khojasteh
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (R.H.T., E.F.C., S.M., S.W., J.H., Y.D., C.E.C.A.H., S.C.K.,), Product Development Oncology (I.R.), Early Clinical Development (M.G.), and Clinical Pharmacology (M.J.D, L.M.), Genentech, South San Francisco, California.
authors.forename: Luna
authors.initials: L
authors.lastname: Musib
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001384:Azetidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001682:Biological Availability; D001711:Biotransformation; D002250:Carbon Radioisotopes; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005998:Glycine / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D065667:Renal Elimination; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D002250:Carbon Radioisotopes; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C574276:cobimetinib; D005998:Glycine