Population pharmacokinetics of TBAJ-587 and its main metabolites-Evaluation of different loading dose strategies and early dose selection

Background and aim The rise of drug-resistant tuberculosis (TB) poses a need for new drugs and combinations. TBAJ-587, a new diarylquinoline (DARQ), has shown promising efficacy in preclinical studies. This work aimed to describe the pharmacokinetics (PK) of TBAJ-587 and its metabolites M2 and M3 after single ascending dosing in healthy volunteers and to develop a simultaneous population PK model. In addition, to explore different doses in relation to efficacy and safety and to assess the impact of loading doses on exposure levels of TBAJ-587 and its metabolites. Methods Pharmacokinetic samples from 42 healthy volunteers following a single dose (25, 50, 100, 200, 400 or 800 mg) were collected for up to Day 126. Population pharmacokinetic modelling was conducted using nonlinear mixed-effects modelling in NONMEM. Simulations from final model were performed to compare against efficacy targets derived from the first-in-class DARQ bedaquiline and safety references based on preclinical studies. Results and conclusions The final model simultaneously described the PK of TBAJ-587, M2 and M3 well. Simulations of final model identified that all simulated doses and regimens resulted in exposures that were below the safety references. A loading dose for 2 weeks resulted in initially higher concentrations, but a limited difference in exposure at 4 weeks and onwards, compared with no loading dose. A 100 mg once daily dose and higher reached the efficacy targets and can be studied further in combinations in phase 2a studies. Name of trial: Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults. Registration number NCT04890535.