Population pharmacokinetics and dose evaluation for second-line TB drugs in patients with diabetes

<sec><title>BACKGROUND</title>To evaluate currently recommended dosage using the population pharmacokinetics (PK) of bedaquiline (BDQ), clofazimine, cycloserine, linezolid (LZD) and moxifloxacin (MFX) in patients with multidrug-resistant TB (MDR-TB) and type II diabetes mellitus (DM).</sec><sec><title>METHODS</title>A prospective multi-centre PK study was conducted in China between 2016 and 2019. Population PK models were developed using nonlinear mixed-effect analyses based on the blood samples collected by rich sampling. The probability of target attainment (PTA) analysis was estimated using the Monte Carlo simulation.</sec><sec><title>RESULTS</title>A total of 1,450 plasma samples were collected from 58 participants with DM. Simulations showed that the WHO-recommended regimens of LZD (600 mg daily) and MFX (400 mg daily) achieved > 90% PTA for <i>M. tuberculosis</i> isolates with MICs below 0.50 and 0.25 mg/L, respectively. The currently recommended BDQ regimen (400 mg daily for 2 weeks, followed by 200 mg thrice weekly) might fail to achieve >90% PTA at an MIC of 0.06 mg/L or higher.</sec><sec><title>CONCLUSION</title>The population PK models for the five second-line drugs were established in Chinese patients with MDR-TB and DM. The model-based dosage evaluation showed that dosing adjustments may be necessary for isolates with borderline resistance levels.</sec>.