Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 102, Issue 9, Pages 3100-3109Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.23519
Keywords
dabrafenib; food effects; particle size; bioavailability; HPMC; gelatin; capsules; supersaturation; dissolution; clinical pharmacokinetics
Funding
- GlaxoSmithKline [NCT01231568]
Ask authors/readers for more resources
Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailabilitywas notedwith nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules. (C) 2013Wiley Periodicals, Inc. and the American Pharmacists Association
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available