GSK2251052 is a member of a novel mechanistic and structural class of antibiotics that inhibits the bacterial enzyme leucyl tRNA synthetase (LeuRS) by forming a boron adduct with tRNA and is currently in development for the treatment of hospital acquired Gramnegative infections.
GSK2251052 is a member of a novel mechanistic and structural class of antibiotics that inhibits the bacterial enzyme leucyl tRNA synthetase (LeuRS) by forming a boron adduct with tRNA and is currently in development for the treatment of hospital acquired Gramnegative infections (including E. coli, K. pneumoniae, and Enterobacter spp.). This is a multi-part study. Part A is a randomized, open-label, single dose, three-period, incomplete block design to evaluate the relative bioavailability of five oral formulations of GSK2251052. Approximately 24 healthy subjects will be enrolled to receive treatment with GSK2251052 at a dose of 2000 mg and randomized to receive three of the following five formulations: 1) enteric-coated tablet (Treatment A), 2) modified release tablet (Treatment B), 3) enteric-coated powder for oral suspension (Treatment C), 4) immediate release tablet (Treatment D), and 5) oral solution (Treatment E). One or two formulations from Part A will be selected on the basis of acceptable safety and pharmacokinetic criteria for further dose evaluation in Part B. If no formulations are deemed to have the desired PK characteristics, Part B will not be conducted. Part B is a randomized, single-blind, placebo-controlled, dose-escalation evaluation of the selected formulation(s) from Part A. Approximately 8 subjects will be randomly assigned to receive GSK2251052 at the planned starting dose of 2000 mg or respective placebo in Period 1. In Period 2, the next dose level will be administered at an increment of 500 mg and/or based on the PK and safety of the preceding period. Additional periods may be conducted with the selected formulation pending acceptable safety in order to achieve target pharmacokinetic concentrations. Part C is a randomized, single-blind, placebo-controlled, two-cohort, two period, crossover study of the selected formulation of GSK2251052 in Part B to evaluate its multiple-dose safety and pharmacokinetics in both young and elderly, male and female healthy volunteers. Approximately 16 subjects will be enrolled (8 per cohort with an equal number of females if possible) and will be randomized to receive either active treatment or placebo for 5 days both fasted and with a meal. Cohorts will be evaluated sequentially, with cohort 1 (young) conducted first, and pending acceptable safety, proceeding with an evaluation in cohort 2 (elderly) subsequently. Part D is identical in design and conduct to Part C except it will evaluate the multipledose pharmacokinetics, safety, and tolerability of an immediate release formulation given thrice daily at a dose of 2000 mg. Part D is conditional and will only be conducted if none of the new formulations demonstrate appropriate pharmacokinetics, safety and tolerability. This study will be conducted at a single center in Australia.
Oral formulation of an an antibacterial
GSK Investigational Site
Adelaide, South Australia, Australia
Single dose relative bioavailability of five formulations
Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.
Time frame: 3 days
Pharamacokinetics of escalating single oral doses
Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.
Time frame: 4 days
To evaluate and compare the pharmacokinetics of multiple oral doses of GSK2251052 in young and elderly healthy adult subjects
Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.
Time frame: Days 1 to 4 and day 9
Safety and tolerability in Part A
Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.
Time frame: Days 1 to 4 and day 14 post-dose in periods 3
Safety and tolerability in Part B
Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.
Time frame: Days 1 to4 and day 14 post dose in period 3
Part C and Part D, to assess the safety and tolerability of GSK2251502 in healthy young and elderly volunteers following single and repeat dose administration with and without food
Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.
Time frame: Days 1 to 4 and day 9 and day 14 post last dose in period 2.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
SINGLE
Enrollment
24