The study is designed to evaluate the effects of a high fat meal on the pharmacokinetics of 150 mg of GSK2118436, as well as the effects of particle size on the relative bioavailability of GSK2118436.
GSK2118436 is an orally administered, potent and selective small molecule BRAF inhibitor that is currently being developed for the treatment of BRAF mutation-positive tumors. This study is designed to evaluate the effects of particle size on the relative bioavailability of GSK2118436 (Cohort 1) and to evaluate the effects of a high-fat meal on the pharmacokinetics of GSK2118436 (Cohort 2). Subjects will randomly receive two of four possible regimens over two periods. Subjects enrolled in Cohort 1 will receive a single 150 mg dose of GSK2118436 as micronized particles fasted (gelatin capsule formulation) and a single 150 mg dose of GSK2118436 as non-micronized particles fasted (larger particle size). Subjects enrolled in Cohort 2 will receive a single 150 mg dose of GSK2118436 (HydroxyPropyl Methyl Cellulose (HPMC) capsule formulation) fasted and with a high-fat breakfast. GSK2118436 will be administered as the mesylate salt (equivalent to 150 mg free base). Safety and tolerability will also be evaluated. The study will be conducted at a sufficient number of centers to complete approximately 28 adult subjects (14 subjects per cohort) with BRAF mutation-positive tumors. Following completion of this study, subjects may continue dosing with GSK2118436 in the roll-over study, Protocol BRF114144.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
28
Two gelatin capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed fasted
Two gelatin capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, larger, non-micronized particles, equivalent to 150 mg free base), dosed fasted
Two Hydroxy Propyl Methyl Cellulose (HPMC) capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed fasted
GSK Investigational Site
Scottsdale, Arizona, United States
GSK Investigational Site
Detroit, Michigan, United States
GSK Investigational Site
Nashville, Tennessee, United States
GSK Investigational Site
Salt Lake City, Utah, United States
Area under the plasma-concentration time curve (AUC) of GSK2118436
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose
Maximum plasma concentration (Cmax) of GSK2118436
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose
Time to Cmax (Tmax) of GSK2118436
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose
Terminal half-life (t1/2) of GSK2118436
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose
AUC, Cmax, Tmax and t1/2 of GSK2118436 metabolites (GSK2285403, GSK2167542 and GSK2298683) and ratio of metabolite to parent drug GSK2118436
Time frame: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, 48, 72 and 96 hours post-dose
Number of subjects with adverse events as a measure of safety and tolerability
Time frame: From date of first dose until transition to rollover protocol BRF114144 (approximately 12 days) or study follow up visit if subject does not transition to BRF114144 (approx 22 days)
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Two HPMC capsules containing 75 mg GSK2118436A (dosed as the mesylate salt, micronized particles, equivalent to 150 mg free base), dosed with a high-fat meal