Model-based dose optimization framework for bedaquiline, pretomanid and linezolid for the treatment of drug-resistant tuberculosis.

ABSTRACT

AIMS: Bedaquiline, pretomanid and linezolid (BPaL) combination treatment against Mycobacterium tuberculosis is promising, yet safety and adherence concerns exist that motivate exploration of alternative dosing regimens. We developed a mechanistic modelling framework to compare the efficacy of the current and alternative BPaL treatment strategies. METHODS: Pharmacodynamic models for each drug in the BPaL combination treatment were developed using in vitro time-kill data. These models were combined with pharmacokinetic models, incorporating body weight, lesion volume, site-of-action distribution, bacterial susceptibility and pharmacodynamic interactions to assemble the framework. The model was qualified by comparing the simulations against the observed clinical data. Simulations were performed evaluating bedaquiline and linezolid approved (bedaquiline 400 mg once daily [QD] for 14 days followed by 200 mg three times a week, linezolid 1200 mg QD) and alternative dosing regimens (bedaquiline 200 mg QD, linezolid 600 mg QD). RESULTS: The framework adequately described the observed antibacterial activity data in patients following monotherapy for each drug and approved BPaL dosing. The simulations suggested a minor difference in median time to colony forming unit (CFU)-clearance state with the bedaquiline alternative compared to the approved dosing and the linezolid alternative compared to the approved dosing. Median time to non-replicating-clearance state was predicted to be 15 days from the CFU-clearance state. CONCLUSIONS: The model-based simulations suggested that comparable efficacy can be achieved using alternative bedaquiline and linezolid dosing, which may improve safety and adherence in drug-resistant tuberculosis patients. The framework can be utilized to evaluate treatment optimization approaches, including dosing regimen and duration of treatment predictions to eradicate both replicating- and non-replicating bacteria from lung and lesions.