Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043.

Introduction: BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure-response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043.

Methods: A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.

Results: In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%-65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043 + M2).

Conclusions: We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.