Effects of particle size, food, and capsule shell composition on the oral bioavailability of dabrafenib, a BRAF inhibitor, in patients with BRAF mutation-positive tumors

J Pharm Sci. 2013 Sep;102(9):3100-9. doi: 10.1002/jps.23519. Epub 2013 Apr 22.


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 bioavailability was noted with 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.

Trial registration: ClinicalTrials.gov NCT01231568.

Keywords: HPMC; bioavailability; capsules; clinical pharmacokinetics; dabrafenib; dissolution; food effects; gelatin; particle size; supersaturation.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / blood*
  • Biological Availability
  • Capsules / chemistry
  • Cohort Studies
  • Fasting
  • Female
  • Humans
  • Hypromellose Derivatives
  • Imidazoles / administration & dosage*
  • Imidazoles / blood*
  • Male
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Methylcellulose / analogs & derivatives
  • Methylcellulose / chemistry
  • Middle Aged
  • Oximes / administration & dosage*
  • Oximes / blood*
  • Particle Size
  • Point Mutation
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics


  • Antineoplastic Agents
  • Capsules
  • Imidazoles
  • Oximes
  • Hypromellose Derivatives
  • Methylcellulose
  • Proto-Oncogene Proteins B-raf
  • dabrafenib

Associated data

  • ClinicalTrials.gov/NCT01231568