@article {Choodmd.115.063743, author = {Edna F Choo and Sarah Woolsey and Kevin DeMent and Justin Ly and Kirsten Messick and Ann Qin and Ryan Takahashi}, title = {Use of Transgenic Mouse Models to Understand the Oral Disposition and Drug-Drug Interaction Potential of Cobimetinib, a MEK Inhibitor}, elocation-id = {dmd.115.063743}, year = {2015}, doi = {10.1124/dmd.115.063743}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 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 IV administration of 1 mg/kg cobimetinib to wild-type (WT; FVB), Cyp3a-/-Tg-3A4Hep, Cyp3a-/-Tg-3A4Int or Cyp3a-/-Tg-3A4Hep/Int mice, CL (26-35 mL/min/kg) was similar in the CYP3A4 transgenic and WT mice. After oral administration of 5 mg/kg cobimetinib, the AUC 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 ~80\% lower AUC of cobimetinib in transgenic mice when intestinal CYP3A4 was present suggested that 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 interactions (DDI) studies using Cyp3a-/-Tg-3A4Hep/Int mice, a 7- and 2-fold increase in oral and IV cobimetinib exposure, respectively, were observed with itraconazole co-administration. In PXR-CAR-CYP3A4/CYP3A7 mice, rifampin induction decreased cobimetinib oral exposure by ~80\%. Collectively, these data are supportive that CYP3A4 intestinal metabolism contributed to the oral disposition of cobimetinib and suggests that under certain circumstances the transgenic model may be useful in predicting clinical DDI.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2015/03/26/dmd.115.063743}, eprint = {https://dmd.aspetjournals.org/content/early/2015/03/26/dmd.115.063743.full.pdf}, journal = {Drug Metabolism and Disposition} }