Pharmacokinetics
Concomitant Oral and Intravenous Pharmacokinetics of Dabrafenib, a BRAF Inhibitor, in Patients With BRAF V600 Mutation‐Positive Solid Tumors
The Journal of Clinical Pharmacology 53(9) 955–961 ©2013, The American College of Clinical Pharmacology DOI: 10.1002/jcph.127
Cathrine L. Denton, PhD1, Elisabeth Minthorn, BS2, Stanley W. Carson, PharmD1, Graeme C. Young, MSc3, Lauren E. Richards‐Peterson, PhD4, Jeffrey Botbyl, MS5, Chao Han, PhD6, Royce A. Morrison, MD7, Samuel C. Blackman, MD, PhD8, and Daniele Ouellet, PhD1
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 mg 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 Tmax 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.
Keywords bioavailability, dabrafenib, pharmacokinetic, intravenous, microtracer
Dabrafenib (GSK2118436) is an orally potent and selective small‐molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation‐positive malignant melanoma. Clinical activity was first observed in a phase 1 first‐time‐ in‐human (FTIH) study,1 and efficacy of oral dabrafenib 150 mg twice daily was confirmed in a randomized phase 3 study2 as well as a phase 2 study in patients with melanoma.3 The pharmacokinetics of dabrafenib after oral administration was characterized in the FTIH study.1 Following a single oral dose of 150 mg dabrafenib, median Tmax was recorded 2 hours after dosing and the mean terminal half‐ life (t1/2) was 5.2 hours. Three major circulating metabolites were identified in the FTIH study and their pharmacokinetics characterized. Based on data from the mass balance study, the half‐lives of hydroxy‐, carboxy‐, and desmethyl‐dabrafenib were 5.7, 17.5, and 20.4 hours, respectively.4 Determination of absolute bioavailability improves our understanding and is required by several regulatory agencies, but such clinical studies have been fraught
with the challenges and delays associated with preparing and administering a drug intravenously that has been developed for oral use. The use of intravenous (IV) radiolabeled microtracer studies offers an attractive alternative to conducting conventional crossover‐design absolute bioavailability studies and provides
1
GlaxoSmithKline, Research Triangle Park, NC, USA GlaxoSmithKline, Collegeville, PA, USA 3 GlaxoSmithKline, Ware, UK 4 GlaxoSmithKline, King of Prussia, PA, USA 5 Provonix, Mullica Hill, NJ, USA 6 Biologics Clinical Pharmacology, Janssen R&D, Spring House, PA, USA 7 Comprehensive Clinical Development, Tacoma, WA, USA 8 Translational Medicine, Seattle Genetics, Inc., Bothell, WA, USA 2
Submitted for publication 8 March 2013; accepted 4 June 2013. Corresponding Author: Cathrine L. Denton, PhD, GlaxoSmithKline, Clinical Pharmacology Modeling & Simulation, 5 Moore Drive, Research Triangle Park, NC 27709, USA E-mail:
[email protected]
956 characterization of the IV pharmacokinetics of a new compound. The microtracer approach involves administration of an unlabeled oral therapeutic dose with concomitant administration of a subtherapeutic radiolabeled IV microdose (pharmacologically inactive). A microdose is defined as less than 1/100th of the calculated clinical dose (based on animal data) needed to yield a pharmacologic effect, up to a maximum of 100 mg.5,6 The radiolabeled microdose produces trivial exposure to ionizing radiation (15% (actual, 15% (actual,
