This is a two-part study. Part A is a three-period study in approximately 24 healthy male Japanese and Caucasian subjects. Period 1 and Period 2 will be an open label study to investigate the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of GSK2251052. Period 3 is a single blind, placebo controlled, repeat fixed dose design to evaluate the safety, tolerability and pharmacokinetics of multiple intravenous doses of GSK2251052 for 12 days. The selection of the repeat IV dose will be based on the results from Periods 1 and 2. Japanese subjects will be stratified based on their metabolic genotype, polymorphic or wild-type for ADH and ALDH. Caucasian subjects are not anticipated to have these enzyme polymorphisms and therefore will not be stratified. Part B is a two cohort, single-blind, randomized, placebo-controlled, dose-rising, repeat dose study in approximately 24 healthy male and female subjects to evaluate the safety, tolerability, and pharmacokinetics of supratherapeutic IV doses of GSK2251052 for 10 days. Cohort 1 subjects will be randomized to receive 2250 mg of GSK2251052 or placebo and Cohort 2 subjects will be randomized to receive 3000 mg GSK2251052 or placebo. The decision to conduct Cohort 2 of Part B will be based on the available toxicology cover results from ongoing preclinical toxicity studies.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
SINGLE
Enrollment
8
Treatment A: 750 mg IV GSK2251052 single dose
Treatment B: 1500 mg IV GSK2251052 single dose
Treatment C: 1500 mg IV GSK2251052 BID or placebo for 12 days
Treatment D: On Day 1 a single dose of GSK2251052 2250 mg IV administered over 60 minutes; Days 4 - 12 BID doses of GSK2251052 2250 mg IV (for 9 days), fasted
Treatment E: On Day 1 a single dose of GSK2251052 3000 mg IV administered over 60 minutes; Days 4 - 12 BID doses of GSK2251052 3000mg IV (for 9 days), fasted
Treatment P: On Day 1 a single dose of 0.9% saline IV administered over 60 minutes; On Days 4 - 12 BID doses of 0.9% saline (for 9 days), fasted
GSK Investigational Site
Glendale, California, United States
Composite (or Profile) of Pharmacokinetics
pharmacokinetic endpoints maximum observed concentration fixed nominal time (Cmax), area under the concentration-time curve from time zero extrapolated to infinite time (AUC(0-∞), area under the concentration-time curve from time zero to last time of quantifiable concentration within a subject across all treatments (AUC(0-t), AUC(0-12), time of occurrence of Cmax (tmax), time of last quantifiable concentration (tlast), terminal phase half-life (t1/2), volume of distribution at steady state (Vss), and Systemic clearance of parent drug (CL) of GSK2251052 and metabolite M3 (as appropriate).
Time frame: Part A: Period 1 for 168 hours post dose; Period 2 for 336 hours post dose; Period 3 on day 12 for 12 hours post dose. Part B: On day 1 for 72 hours post dose; on day 12 for 12 hours post dose.
Safety and tolerability parameters including change from baseline measures for vital signs
Time frame: Part A: for 15 weeks. Part B: for 9 weeks
Safety and tolerability parameters including change from baseline for ECGs
Time frame: Part A: for 15 weeks. Part B: for 9 weeks
Safety and tolerability parameters including change from baseline for clinical laboratory tests
hematology, chemistry, and urinalysis
Time frame: Part A: for 15 weeks. Part B: for 9 weeks
Safety and tolerability parameters including change from baseline in the collection of adverse events
Time frame: Part A: for 15 weeks. Part B: for 9 weeks
Composite (or Profile) of Pharmacokinetics
Observed accumulation based on (AUC(Ro) and Cmax (RCmax) and determine the steady-state ratio (Rss)
Time frame: Part A: Period 1 for 168 hours post dose; Period 2 for 336 hours post dose; Period 3 on day 12 for 12 hours post dose. Part B: On day 1 for 72 hours post dose; on day 12 for 12 hours post dose.
Composite or Profile of Pharmacokinetics
AUC(0-∞), AUC(0-t), and Cmax following IV administration at different doses for the assessment of dose proportionality
Time frame: Part A: Period 1 for 168 hours post dose; Period 2 for 336 hours post dose; Period 3 on day 12 for 12 hours post dose. Part B: On day 1 for 72 hours post dose; on day 12 for 12 hours post dose.
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