Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.
J Clin Pharmacol
; 55(4): 392-400, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25449654
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- ∞) decreased 37% and Cmax 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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oximas
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Genfibrozila
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Imidazóis
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Cetoconazol
Tipo de estudo:
Clinical_trials
Limite:
Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos