Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.

Article Details

Citation

Copy to clipboard

Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, LoRusso PM, Infante JR, Sharma S, Kendra K, Patel M, Pant S, Arkenau HT, Middleton MR, Blackman SC, Botbyl J, Carson SW

Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.

J Clin Pharmacol. 2015 Apr;55(4):392-400. doi: 10.1002/jcph.437. Epub 2014 Dec 30.

PubMed ID

25449654 [ View in PubMed

]

Abstract

The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- infinity) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- tau) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-tau) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-tau) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dabrafenib	Cytochrome P450 2C9	Protein	Humans	No	Substrate Inhibitor Inducer	Details