GSK2118436 is an orally administered, potent and selective small molecule BRAF inhibitor that is being developed for the treatment of BRAF mutation-positive tumors. This is a 4-part study (in 4 separate cohorts of subjects) designed to examine the interaction potential of GSK2118436, either as a perpetrator (i.e., effect of GSK2118436 on warfarin; Part A) or victim (i.e., effect of other drugs on GSK2118436; Part B: ketoconazole and Part C: gemfibrozil), as well as to evaluate the single and repeat dose pharmacokinetic parameters of GSK2118436 (Part D). A sufficient number of subjects will be screened to obtain approximately 12 evaluable subjects each for Part A, Part B, Part C and Part D. Following completion of this study, subjects may continue dosing with GSK2118436 in the roll-over study, Protocol BRF114144.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
Warfarin dosed at 15mg on Day 1 and Day 22
Ketoconazole dosed at 400mg daily on Days 19 through 22
Gemfibrozil dosed at 600mg twice daily on Days 19 through 22
GSK2118436 dosed at 150mg twice daily
GSK2118436 dosed at 75mg twice daily
GSK Investigational Site
Scottsdale, Arizona, United States
GSK Investigational Site
Sarasota, Florida, United States
GSK Investigational Site
Detroit, Michigan, United States
GSK Investigational Site
Columbus, Ohio, United States
GSK Investigational Site
Oklahoma City, Oklahoma, United States
GSK Investigational Site
Greenville, South Carolina, United States
GSK Investigational Site
Nashville, Tennessee, United States
GSK Investigational Site
Salt Lake City, Utah, United States
GSK Investigational Site
Nedlands, Western Australia, Australia
GSK Investigational Site
Headington, United Kingdom
...and 1 more locations
Maximum plasma concentration (Cmax) of S-warfarin with and without GSK2118436
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Area under the concentration time curve (AUC) of S-warfarin with and without GSK2118436
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Maximum plasma concentration (Cmax) of GSK2118436 with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Area under the concentration time curve (AUC) of GSK2118436 with and without an inhibitor
Time frame: Up to12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Cmax of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
AUC of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Time to Cmax (Tmax) of GSK2118436 and metabolites after single and multiple 75mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Half-life of GSK2118436 and metabolites after single 75mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1
Cmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
AUC of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Tmax of GSK2118436 and metabolites after single and multiple 150mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1 and up to 12 hours after dosing on Day 18
Half-life of GSK2118436 and metabolites after single 150mg HPMC dose
Time frame: Up to 24 hours after dosing on Day 1
Cmax of R-warfarin with and without GSK2118436
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Time to Cmax (Tmax) of R-warfarin
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Trough concentration of GSK2118436
Time frame: Up to168 hours after dosing on Day 22
Number of subjects with adverse events as a measure of safety and tolerability
Time frame: From date of first dose to transition to Rollover protocol BRF114144 (22 - 29 days) or study follow up visit if subject does not transition to BRF114144 (approximately 29 - 39 days)
Tmax for GSK2118436 with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
AUC, Cmax, Tmax and trough concentration of GSK2118436 metabolites with and without an inhibitor, and AUC ratio of metabolites to parent
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Inhibitor concentrations in combination with GSK2118436
Time frame: Up to12 hours after dosing on Day 22 (GSK2118436 in combination with inhibitor)
AUC of R-warfarin with and without GSK2118436
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
Terminal half-life (t1/2) of R-warfarin
Time frame: Up to 168 hours after dosing on Day 1 (warfarin alone) and Day 22 (warfarin in combination with GSK2118436)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Cmax of GSK2118436
Time frame: Up to168 hours after dosing on Day 22
Trough concentration for GSK2118436 with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Cmax of GSK2118436 metabolites with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Tmax of GSK2118436 metabolites with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
Trough concentration of GSK2118436 metabolites with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)
AUC ratio of metabolites to parent with and without an inhibitor
Time frame: Up to 12 hours after dosing on Day 18 (GSK2118436 alone) and Day 22 (GSK2118436 in combination with inhibitor)