The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk.
Article Details
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Lawrence SK, Nguyen D, Bowen C, Richards-Peterson L, Skordos KW
The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk.
Drug Metab Dispos. 2014 Jul;42(7):1180-90. doi: 10.1124/dmd.114.057778. Epub 2014 Apr 18.
- PubMed ID
- 24748562 [ View in PubMed]
- 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 muM. 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 muM. Hydroxy-dabrafenib inhibited CYP1A2, 2C9, and 3A4 (midazolam) with calculated IC50 values of 83, 29, and 44 muM, 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 muM, respectively. At 30 muM 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dabrafenib Cytochrome P450 1A2 Protein Humans NoInhibitorDetails Dabrafenib Cytochrome P450 2B6 Protein Humans NoInhibitorInducerDetails Dabrafenib Cytochrome P450 2C19 Protein Humans NoSubstrateInhibitorInducerDetails Dabrafenib Cytochrome P450 2C8 Protein Humans NoSubstrateInhibitorDetails Dabrafenib Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorInducerDetails Nicardipine Cytochrome P450 2C8 Protein Humans UnknownSubstrateInhibitorDetails