Albin Leding1, Paul Bruinenberg2, Almari Conradie2, Jerry Nedelman2, Antonio Lombardi2, Dean Hickman2, Ulrika S.H. Simonsson1
1Department of Pharmaceutical Biosciences, Uppsala University, 2TB Alliance
Introduction/objective: Diarylquinolines (DARQs) have become essential in treatment regimens against Mycobacterium tuberculosis. TBAJ-587 is a 2nd generation DARQ being developed by TB Alliance. This DARQ shows promising efficacy and safety in preclinical studies. From TBAJ-587, two main active metabolites are formed (M2 and M3). This work aims to utilize pharmacokinetic data of TBAJ-587 and its metabolites M2 and M3 from a phase 1a trial to make dose and regimen recommendations based on efficacy and safety. Methods: Pharmacokinetic data were available from partially blinded SAD phase 1 trial (TBAJ-587-CL001 [NCT04890535])(1) with six oral dose cohorts (in mg: 25 [n=6], 50 [n=4], 100 [n=5], 200 [n=8], 400 [n=4], 800 [n=6]) and one food effect cohort (200 mg [n=9]). Data included 42 healthy adults with a total of 5787 observations up to 126 days, with observations of TBAJ-587 and the metabolites, M2 and M3, at each time point. The total of below-limit-of-quantification observations was 25% and for TBAJ-587, M2 and M3 2%, 46% and 28%, respectively. The data was used to develop a population pharmacokinetic model for TBAJ-587 and metabolites. The developed population pharmacokinetic model was utilized to explore regimens in regard to efficacy and safety. Efficacy targets for simulations from the final model were derived with an exposure-matching strategy to the first-in-class DARQ, bedaquiline. The efficacy target was derived as the potency-corrected average concentration profile of label-dosed bedaquiline as well as accounting for the metabolites of bedaquiline and TBAJ-587. Safety references were derived from a 3-month dog toxicity study. The regimens simulated were dosing daily for 12 weeks of which the first 2 weeks could be loading periods. Maintenance dosages explored were 25, 50, 100 or 200 mg daily. Loading doses explored were 2, 3 or 4 times the maintenance dose. Regimens were evaluated towards the efficacy targets. NONMEM v7.5.0 and PsN v5.0.0 were utilized for model development and evaluation. Simulations from the final model were performed with the package deSolve (version 1.33) in R (version 4.1.2). Results: The developed model described the concentrations of TBAJ-587, M2, and M3 well. TBAJ-587 and M3 were described with a three-compartmental disposition model, and M2 was described with a two-compartmental disposition model. Absorption of TBAJ-587 was captured with a transit compartment model and elimination was described with a dose-dependent apparent clearance of 5.40 L/h after a 200 mg dose. Metabolite formation was independent and formed directly via TBAJ-587 elimination. M2 also showed dose-dependent apparent clearance of 34.1 L/h after a 200 mg dose while M3 didn’t and had an apparent clearance of 18.5 L/h. The predicted daily area under the curves (AUC[0-24 h]) for regimens without loading dose period were at the end of week four for TBAJ-587; 25 mg = 2.08 h×mg/L, 200 mg = 15.1 h×mg/L, for M2; 25 mg = 0.139 h×mg/L, 200 mg = 0.734 h×mg/L and for M3; 25 mg = 0.296 h×mg/L, 200 mg = 1.69 h×mg/L. Increases in predicted exposure were approximately dose-proportional for TBAJ-587, slightly less so for M2 and M3. The lowest dosing regimen without a loading dose that reached the efficacy target was 100 mg once daily for 12 weeks. At four weeks, the exposure was similar between no loading doses and loading doses. Conclusions: With the early dose recommendation approach, simulations using efficacy targets and safety references identified that doses in the range 25-200 mg daily are safe and a 100 mg daily regimen, with or without loading doses, reaches efficacy targets and can be studied further in combinations in Phase 2a studies. Reference: [1] Global Alliance for TB Drug Development, Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults, clinicaltrials.gov, NIH; 2021, [accessed Jan 27, 2025]. Available from: https://clinicaltrials.gov/study/NCT04890535
Reference: PAGE 33 (2025) Abstr 11527 [www.page-meeting.org/?abstract=11527]
Poster: Drug/Disease Modelling - Infection