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Assessment of the drug interaction potential and single‐ and repeat‐dose pharmacokinetics of the BRAF inhibitor dabrafenib
Author(s) -
Suttle A. Benjamin,
Grossmann Kenneth F.,
Ouellet Daniele,
RichardsPeterson Lauren E.,
Aktan Gursel,
Gordon Michael S.,
LoRusso Patricia M.,
Infante Jeffrey R.,
Sharma Sunil,
Kendra Kari,
Patel Manish,
Pant Shubham,
Arkenau HendrikTobias,
Middleton Mark R.,
Blackman Samuel C.,
Botbyl Jeff,
Carson Stanley W.
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.437
Subject(s) - dabrafenib , pharmacokinetics , pharmacology , cyp2c8 , medicine , cmax , gemfibrozil , drug interaction , cyp2c9 , cyp3a , vemurafenib , cancer , cytochrome p450 , metabolism , metastatic melanoma , cholesterol
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– ∞ decreased 37% and C max increased 18% with dabrafenib. Dabrafenib AUC 0– τ and C max increased 71% and 33%, respectively, with ketoconazole. Hydroxy‐ and desmethyl‐dabrafenib AUC 0–τ increased 82% and 68%, respectively, and AUC for carboxy‐dabrafenib decreased 16%. Dabrafenib AUC 0–τ 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.