First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment

Antimicrob Agents Chemother. 2019 Jul 25;63(8):e00240-19. doi: 10.1128/AAC.00240-19. Print 2019 Aug.


This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0-τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0-14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at under identifier NCT03075410.).

Keywords: EBA prediction; FTIH; GSK3036656; clinical trial simulations; dose escalation; dose rationale; food effect; pharmacokinetics; repeat dose; safety; single dose; tolerability; tuberculosis.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / adverse effects
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology*
  • Area Under Curve
  • Boron Compounds / administration & dosage
  • Boron Compounds / adverse effects
  • Boron Compounds / pharmacokinetics
  • Boron Compounds / pharmacology*
  • Double-Blind Method
  • Enzyme Inhibitors / pharmacology
  • Female
  • Food
  • Heterocyclic Compounds, 2-Ring / administration & dosage
  • Heterocyclic Compounds, 2-Ring / adverse effects
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Leucine-tRNA Ligase / antagonists & inhibitors
  • Male
  • Middle Aged
  • Models, Biological
  • Placebos
  • Tuberculosis / drug therapy*
  • Young Adult


  • Antitubercular Agents
  • Boron Compounds
  • Enzyme Inhibitors
  • GSK656
  • Heterocyclic Compounds, 2-Ring
  • Placebos
  • Leucine-tRNA Ligase

Associated data