This study is a Phase I, two-part, open-label study designed to evaluate the effect of repeated doses of GSK2586184 on the pharmacokinetics (PK) of Simvastatin and Rosuvastatin in healthy volunteers (Cohort A), and to evaluate the pharmacokinetics of a new tablet formulation of GSK2586184 in healthy male volunteers (Cohort B). Cohort A is a single sequence drug interaction study in which 28 subjects (14 female and 14 male subjects) will be enrolled. Each subject will receive single doses of Simvastatin and Rosuvastatin on two occasions, once alone and once following administration of repeated doses of GSK2586184. Cohort B is a 3-way crossover PK study in which 9 male subjects will be randomized (3 subjects to each treatment sequence). Each subject will receive a single dose of the standard formulation of GSK2586184 with food and two doses of a new formulation of GSK2586184, once with food and once in a fasted state, according to their treatment sequence, with a 3-day wash out between doses. The primary aim of the study is to investigate the effects of GSK2586184 on the pharmacokinetics of the 2 statins and to assess the impact of dosing with and without food on a new formulation of GSK2586184 tablet.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
37
GSK2586184 standard formulation is a white film coated round biconvex 200 mg oral tablet. For cohort A, it is to be administered at 400 mg (200 mg x 2 tablets) twice daily from Day 6 to Day 14. For cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose after standard breakfast either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day wash out period.
Simvastatin 10 mg oral tablet is peach-coloured, oval-shaped tablets. It is to be administered orally as a single dose of 10 mg tablet on the mornings of Day 1 and Day 10.
GSK2586184 new formulation without poloxamer is a white film coated round biconvex 200 mg oral tablet. In cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose once after standard breakfast and once after overnight fasting, either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day washout period.
GSK2586184 new formulation without poloxamer is a white film coated round biconvex 200 mg oral tablet. In cohort B, it is to be administered at 400 mg (200 mg x 2 tablets) single dose once after standard breakfast and once after overnight fasting, either on Day 1, 4 and 7 according to the treatment sequence, each separated by a 3-day washout period.
GSK Investigational Site
Baltimore, Maryland, United States
Cohort A: AUC (zero to infinity), AUC (0-t) and Cmax of Rosuvastatin alone and in the presence of GSK2586184
Blood samples will be collected to analyse PK parameters of Rosuvastatin including area under the plasma concentration-time curve from time zero to infinity \[AUC(0-inf)\], area under the plasma concentration-time curve from time zero to the last quantifiable concentration \[AUC(0-t)\] and the maximum observed plasma concentration (Cmax).
Time frame: Days 3 and 12 (1 hour (h) pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours (hrs) post-dose)
Cohort A: AUC (zero to infinity), AUC(0-t) and Cmax of Simvastatin/Simvastatin acid alone and in the presence of GSK2586184.
Blood samples will be collected to analyse PK parameters of Simvastatin including AUC(0-inf), AUC(0-t) and Cmax.
Time frame: Days 1 and 10 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24 and 48 hrs post-dose)
Cohort B: AUC (zero to infinity), AUC(0-24), Tmax and Cmax of GSK2586184 (standard formulation, containing poloxamer) and GSK2586184 (new formulation, without-poloxamer).
Blood samples will be collected to analyse PK parameters of GSK2586184 (standard and new formulation) including AUC(0-inf), area under the plasma concentration-time curve from time 0 to 24 hrs (AUC(0-24)), time to maximum observed plasma drug concentration (Tmax) and Cmax.
Time frame: Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24)
Cohort B: AUC(zero to infinity), AUC(0-24), Tmax and Cmax of GSK2586184 (new formulation, without-poloxamer) dosed with and without food.
Blood samples will be collected to analyse PK parameters of GSK2586184 (new formulation, without-poloxamer) including AUC (0-inf), AUC(0-24), Tmax and Cmax.
Time frame: Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24)
Cohort A: AUC(0-12) and Cmax of GSK2586184 at steady state
Blood samples will be collected to analyse PK parameters of GSK2586184 at steady state including area under the plasma concentration-time curve from time 0 to 12 h (AUC (0-12)) and Cmax.
Time frame: Day 9 (1 h pre-dose, and 0.5, 1, 2, 4, 6, 8, 10 and 12 hrs post dose)
Cohort A: AUC (0-12) and Cmax of two metabolites of GSK2586184 (GSK2983628 and GSK3100466) at steady state
Blood samples will be collected to analyse PK parameters of GSK2983628 and GSK3100466 at steady state including AUC (0-12) and Cmax.
Time frame: Day 9 (1 h pre-dose, and 0.5, 1, 2, 4, 6, 8, 10 and 12 hrs post dose)
Cohort B: AUC (zero to infinity), AUC(0-24), Cmax, Tmax and t1/2 of two metabolites of GSK2586184 (GSK2983628 and GSK3100466)
Blood samples will be collected to analyse PK parameters of GSK2983628 and GSK3100466 including AUC (0-inf), AUC (0-24), Cmax, Tmax and terminal phase half-life (t1/2).
Time frame: Day 1, 4 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hrs post dose) and Day 7 (1 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24)
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