Sudapyridine

Although bedaquiline (BDQ) received conditional approval for multi-drug resistance tuberculosis (MDR-TB), a black box warning was added due to QT prolongation risk. WX-081, a promising second-in-class drug that finished phase II clinical trial, exhibited comparable anti-TB activity and better cardiac safety. The accumulation of its active metabolite WX-081-M3 leads to QT prolongation, whereas the relationships between dosage, exposure and response have not been established. Accordingly, the dosage design for phase III study is challenging. Here, the first population pharmacokinetic (PPK) and exposure-response (E-R) analysis were conducted for WX-081. 1610 WX-081 and 1580 WX-081-M3 concentrations were collected from 24 healthy volunteers and 48 tuberculosis patients for PPK study. The pharmacokinetic parameters and sputum culture conversions of 20 MDR-TB patients receiving BDQ and WX-081 were used for E-R analysis. The absorption of WX-081 was well described by a three-compartments transit model, while the distribution and elimination profiles of WX-081 and WX-081-M3 were captured by three- and two-compartments models, respectively. E-R analysis demonstrated that the clinical efficacy of WX-081 is comparable with BDQ and can be evaluated by average concentration at steady state (C_avg,ss) of WX-081. According to the simulation results of different regimens, the dosage of 450 mg once daily (QD) for 1 week and subsequent 300 mg QD for 1 week followed by 150 mg QD for 22 weeks was recommended considering both efficacy and safety. Our study revealed the PK and efficacy profiles of WX-081 for the first time and proposed a dose optimization strategy to facilitate its clinical development.