title: The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk.
abstract: Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant b-rapidly accelerated fibrosarcoma (b-raf) kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in human liver microsomes, recombinant human cytochrome P450 (P450) enzymes, and human hepatocytes to investigate the potential of dabrafenib and its major circulating metabolites to perpetrate pharmacokinetic drug-drug interactions (DDIs) as well as have their own pharmacokinetics affected (victim) by coadministered drugs. Dabrafenib metabolism was mediated by CYP2C8 (56% to 67%) and CYP3A4 (24%); in addition, it has demonstrated inhibition of CYP2C8, 2C9, 2C19, 3A4 (atorvastatin), and (nifedipine), with calculated IC50 values of 8.2, 7.2, 22.4, 16, and 32 μM. It also demonstrated metabolism-dependent inhibition of CYP3A4 with a maximal inactivation rate constant of 0.040 minute(-1) and a concentration required to achieve half-maximal inactivation for CYP3A4 of 38 μM. Hydroxy-dabrafenib inhibited CYP1A2, 2C9, and 3A4 (midazolam) with calculated IC50 values of 83, 29, and 44 μM, and carboxy-dabrafenib did not inhibit any of the P450 enzymes tested. Desmethyl-dabrafenib inhibited CYP2B6, 2C8, 2C9, 2C19, and 3A4 (midazolam, atorvastatin, and nifedipine) with calculated IC50 values of 78, 47, 6.3, 36, 17, 20, and 28 μM, respectively. At 30 μM dabrafenib showed increases in CYP2B6 and CYP3A4 mRNA expression indicative of induction. The potential clinical relevance of these findings was explored by using mechanistic static mathematical models to estimate the magnitude of change (area under the curve change) as a result of P450-mediated DDI interactions. This risk-assessment approach indicated that dabrafenib is unlikely to perpetrate any in vivo DDIs by inhibition mechanisms, but is a likely inducer of CYP3A4 and a victim of CYP3A4 and CYP2C8 inhibitors. Furthermore, inclusion of the in vitro drug interaction data for dabrafenib metabolites did not impact the overall clinical risk assessment.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Lawrence
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Dung
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Chet
authors.initials: C
authors.lastname: Bowen
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Lauren
authors.initials: L
authors.lastname: Richards-Peterson
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania kon.skordos@novartis.com.
authors.forename: Konstantine W
authors.initials: KW
authors.lastname: Skordos
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D010091:Oximes / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C561627:dabrafenib