title: Concomitant oral and intravenous pharmacokinetics of dabrafenib, a BRAF inhibitor, in patients with BRAF V600 mutation-positive solid tumors.
abstract: Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median T(max) after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA. cathrine.l.denton@gsk.com
authors.forename: Cathrine L
authors.initials: CL
authors.lastname: Denton
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Minthorn
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Carson
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Young
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Richards-Peterson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Botbyl
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Royce A
authors.initials: RA
authors.lastname: Morrison
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Blackman
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D001682:Biological Availability; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D010091:Oximes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: bioavailability; dabrafenib; intravenous; microtracer; pharmacokinetic