Pharmacokinetics, bactericidal activity and toxicity of short oral regimens for rifampicin-resistant tuberculosis treatment

Summary WHO recommends bedaquiline-pretomanid-linezolid-(BPaL) and BPaL-moxifloxacin (BPaLM) for treatment of rifampicin-resistant tuberculosis, informed by the TB-PRACTECAL results. However, clinical explanatory data of these drugs’ exposure and Mycobacterium tuberculosis clearance rates and toxicity relationships remain understudied. We therefore investigated the relationship between the patients’ exposure to anti-TB drugs in TB-PRACTECAL trial investigational regimens and their treatment outcomes. PRACTECAL-PKPD was a prospective pharmacokinetics and pharmacodynamics study nested in TB-PRACTECAL. Patients with rifampicin-resistant pulmonary tuberculosis were enrolled from Belarus and South Africa. The first objective was to develop drug exposure metrics for bedaquiline, pretomanid, linezolid, moxifloxacin and clofazimine. The efficacy objectives were to establish an exposure-response model for each drug and regimen to both bactericidal activity and long-term treatment outcomes. The safety objective was to investigate the exposure-toxicity relationship of each drug. Antimicrobial exposure did not correlate with the speed of sputum bacterial clearance, however there was a 20% increased bacillary killing rate with BPaLM compared to the standard of care arm whilst BPaL and BPaL-clofazimine (BPaLC) displayed a 15% decreased bacillary killing rate compared to the standard of care arm. Linezolid plasma exposure was higher amongst patients with anaemia or neutropenia compared to those without. No other exposure-toxicity relationships were identified for all other drugs. Absence of correlation between drug exposure and bacillary clearance suggest that the dosages used achieve saturation of bacillary killing, while remaining safe. The study was registered in Clinical Trials.gov, TRN: NCT04081077 . Funding Médecins Sans Frontières.