PI-008 - POPULATION MODELING OF GSK3036656 PHARMACOKINETICS AND EARLY BACTERICIDAL ACTIVITY.

S. Lavezzi¹, L. Iavarone², P. Gamallo³, A. Novakovic⁴, C. Chen⁵, G. Vlasakakis⁵; ¹Parexel International, Durham, NC, Ireland, ²Parexel International, London, England, United Kingdom, ³GlaxoSmithKline, Tres Cantos, Madrid, Spain, ⁴Parexel International, Belgrade, Serbia, ⁵GlaxoSmithKline, London, England, United Kingdom.

Background: GSK3036656 is a potent anti-tuberculosis (TB) drug with a novel mechanism of action, currently being investigated in Phase 2 combination trials. A first-in-human (FIH) study (NCT03075410) in healthy subjects (HS) was conducted and a two-compartment population pharmacokinetic (popPK) model developed [1]. A translational two-state bacterial (2SB) model [2] was used to predict early bactericidal activity over 14 days (EBA0–14) [1]. The objective of this work was to update the popPK model and validate the 2SB model based on data from the monotherapy EBA study (NCT03557281) in drug-sensitive TB patients (TBP).

Methods: The FIH study assessed GSK3036656 single doses of 5, 15, and 25 mg, and repeat doses of 5 and 15 mg once daily (QD) for 14 days; the EBA study assessed doses of 1, 5, 15, and 30 mg QD for 14 days (with loading dose on Day 1). The popPK model was fitted to the combined dataset (HS, 959 samples, N=26; TBP, 636 samples, N=49) and covariates were evaluated. EBA simulations were performed, scaling 2SB parameters from mice to humans and adapting the model with pre-treatment bacterial counts. The simulated EBA0–14 values were compared with those observed in the monotherapy EBA study. The analysis was performed using NONMEM 7.4 and R 4.1.

Results: Clearances and volumes increased with body weight. Higher creatinine clearance (CrCL) and lower dose were associated with faster oral clearance. TBP had larger central volume than HS. Exposure is expected to be relevantly impacted (+ >20%) by CrCL. Variability in PK was low (CV <~30%), except for central volume (CV >100%). Median clinical EBA0–14 and PK-2SB simulations were aligned, with higher variability for observed data.

Conclusion: EBA0–14 simulated by a translational 2SB model confirmed the pattern of clinical outcome, although observed data were notably more variable.

[1] Tenero, D. et al. 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. 63, e00240-19 (2019).
[2] Muliaditan, M. & Della Pasqua, O. Evaluation of pharmacokinetic-pharmacodynamic relationships and selection of drug combinations for tuberculosis. Br. J. Clin. Pharmacol. 87, 140–151 (2021).