title: Use of transgenic mouse models to understand the oral disposition and drug-drug interaction potential of cobimetinib, a MEK inhibitor.
abstract: Data from the clinical absolute bioavailability (F) study with cobimetinib suggested that F was lower than predicted based on its low hepatic extraction and good absorption. The CYP3A4 transgenic (Tg) mouse model with differential expression of CYP3A4 in the liver (Cyp3a(-/-)Tg-3A4Hep) or intestine (Cyp3a(-/-)Tg-3A4Int) and both liver and intestine (Cyp3a(-/-)Tg-3A4Hep/Int) were used to study the contribution of intestinal metabolism to the F of cobimetinib. In addition, the effect of CYP3A4 inhibition and induction on cobimetinib exposures was tested in the Cyp3a(-/-)Tg-3A4Hep/Int and PXR-CAR-CYP3A4/CYP3A7 mouse models, respectively. After i.v. administration of 1 mg/kg cobimetinib to wild-type [(WT) FVB], Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice, clearance (CL) (26-35 ml/min/kg) was similar in the CYP3A4 transgenic and WT mice. After oral administration of 5 mg/kg cobimetinib, the area under the curve (AUC) values of cobimetinib in WT, Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice were 1.35, 3.39, 1.04, and 0.701 μM⋅h, respectively. The approximately 80% lower AUC of cobimetinib in transgenic mice when intestinal CYP3A4 was present suggested that the intestinal first pass contributed to the oral CL of cobimetinib. Oxidative metabolites observed in human circulation were also observed in the transgenic mice. In drug-drug interaction (DDI) studies using Cyp3a(-/-)Tg-3A4Hep/Int mice, 8- and 4-fold increases in oral and i.v. cobimetinib exposure, respectively, were observed with itraconazole co-administration. In PXR-CAR-CYP3A4/CYP3A7 mice, rifampin induction decreased cobimetinib oral exposure by approximately 80%. Collectively, these data support the conclusion that CYP3A4 intestinal metabolism contributes to the oral disposition of cobimetinib and suggest that under certain circumstances the transgenic model may be useful in predicting clinical DDIs.
authors: Genentech Inc., South San Francisco, California choo.edna@gene.com.
authors: Edna F
authors: EF
authors: Choo
authors: Genentech Inc., South San Francisco, California.
authors: Sarah
authors: S
authors: Woolsey
authors: Genentech Inc., South San Francisco, California.
authors: Kevin
authors: K
authors: DeMent
authors: Genentech Inc., South San Francisco, California.
authors: Justin
authors: J
authors: Ly
authors: Genentech Inc., South San Francisco, California.
authors: Kirsten
authors: K
authors: Messick
authors: Genentech Inc., South San Francisco, California.
authors: Ann
authors: A
authors: Qin
authors: Genentech Inc., South San Francisco, California.
authors: Ryan
authors: R
authors: Takahashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001384:Azetidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000009:adverse effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D048369:MAP Kinase Kinase 1; C574276:cobimetinib