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

Abstract

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).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.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 M. tuberculosis 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.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..