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.