title: 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.
abstract: 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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA. daniele.x.ouellet@gsk.com
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Grossmann
authors.forename: Giselle
authors.initials: G
authors.lastname: Limentani
authors.forename: Noelia
authors.initials: N
authors.lastname: Nebot
authors.forename: Kevin
authors.initials: K
authors.lastname: Lan
authors.forename: Lara
authors.initials: L
authors.lastname: Knowles
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Girish
authors.initials: G
authors.lastname: Pande
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Krachey
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Blackman
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Carson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000097:blood*; D001682:Biological Availability; D002214:Capsules / Q000737:chemistry; D015331:Cohort Studies; D005215:Fasting; D005260:Female; D006801:Humans; D065347:Hypromellose Derivatives; D007093:Imidazoles / Q000008:administration & dosage* / Q000097:blood*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008875:Middle Aged; D010091:Oximes / Q000008:administration & dosage* / Q000097:blood*; D010316:Particle Size; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002214:Capsules; D007093:Imidazoles; D010091:Oximes; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: HPMC; bioavailability; capsules; clinical pharmacokinetics; dabrafenib; dissolution; food effects; gelatin; particle size; supersaturation