title: Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.
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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Grossmann
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Richards-Peterson
authors.forename: Gursel
authors.initials: G
authors.lastname: Aktan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Kari
authors.initials: K
authors.lastname: Kendra
authors.forename: Manish
authors.initials: M
authors.lastname: Patel
authors.forename: Shubham
authors.initials: S
authors.lastname: Pant
authors.forename: Hendrik-Tobias
authors.initials: HT
authors.lastname: Arkenau
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Blackman
authors.forename: Jeff
authors.initials: J
authors.lastname: Botbyl
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Carson
mesh_terms: D000925:Anticoagulants / Q000493:pharmacokinetics; D065687:Cytochrome P-450 CYP2C8 Inhibitors / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D014859:Warfarin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D015248:Gemfibrozil; C561627:dabrafenib; D007654:Ketoconazole
keywords: CYP2C8; CYP2C9; CYP3A; dabrafenib; drug interaction