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

The exposure and both Mycobacterium tuberculosis clearance rates and toxicity relationships of bedaquiline-pretomanid-linezolid- (BPaL), BPaL-clofazimine (BPaLC) and BPaL-moxifloxacin (BPaLM) for treatment of rifampicin-resistant tuberculosis remain understudied. Therefore, the relationship between the patients’ exposure to anti-TB drugs in TB-PRACTECAL trial investigational regimens and their treatment outcomes was investigated. PRACTECAL-PKPD was a prospective pharmacokinetics and pharmacodynamics study. Patients with rifampicin-resistant tuberculosis were enrolled from Belarus and South Africa. Antimicrobial exposures for bedaquiline, pretomanid, linezolid, moxifloxacin and clofazimine were adequately estimated, were within the ranges of previously published studies but did not correlate with the speed of sputum bacterial clearance. When compared to the standard of care (SoC) arm, a 20% increased bacillary killing rate with BPaLM was observed, whilst BPaL and BPaLC displayed a 15% decreased rate. Also of note was a 20% decreased bacillary killing rate in patients with severe disease irrespective of treatment. Linezolid exposure was higher amongst patients with anaemia or neutropenia. No other exposure-toxicity relationships were identified for all other drugs. These data indicate that the studied doses of linezolid and moxifloxacin could be the right balance between effectiveness and safety, strengthening the WHO recommendation that BPaLM is the preferred regimen for rifampicin-resistant tuberculosis in adolescents and adults. The study was registered in Clinical Trials.gov, TRN: NCT04081077.