title: Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation.
abstract: Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions.
  
  
  
  A physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data. It was then optimized and verified using clinical pharmacokinetic data and itraconazole-cobimetinib DDI data. The contribution of CYP3A4 to the clearance of cobimetinib in humans was confirmed using sensitivity analysis in a retrospective simulation of itraconazole-cobimetinib DDI data. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors and inducers on cobimetinib pharmacokinetics.
  
  
  
  The PBPK model described cobimetinib pharmacokinetic profiles after both intravenous and oral administration of cobimetinib well and accurately simulated the itraconazole-cobimetinib DDI. Sensitivity analysis suggested that CYP3A4 contributes ~78 % of the total clearance of cobimetinib. The PBPK model predicted no change in cobimetinib exposure (area under the plasma concentration-time curve, AUC) with the weak CYP3A inhibitor fluvoxamine and a three to fourfold increase with the moderate CYP3A inhibitors, erythromycin and diltiazem. Similarly, cobimetinib exposure in the presence of strong (rifampicin) and moderate (efavirenz) CYP3A inducers was predicted to decrease by 83 and 72 %, respectively.
  
  
  
  This study demonstrates the value of using PBPK simulation to assess the clinical DDI risk inorder to provide dosing instructions with other CYP3A4 perpetrators.
authors.affiliation: Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Nageshwar R
authors.initials: NR
authors.lastname: Budha
authors.affiliation: Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Ji
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.
authors.forename: Steve
authors.initials: S
authors.lastname: Eppler
authors.affiliation: Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Dresser
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. chen.yuan@gene.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Jin
mesh_terms: D000284:Administration, Oral; D000480:Alkynes; D019540:Area Under Curve; D001384:Azetidines / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000494:pharmacology; D003198:Computer Simulation; D003521:Cyclopropanes; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D010880:Piperidines / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000480:Alkynes; D001384:Azetidines; D048588:Benzoxazines; D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; C574276:cobimetinib; C098320:efavirenz; D016666:Fluvoxamine; D012293:Rifampin