Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment

Objectives: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR -TB) treatment, as well as to identify predictive drug exposure thresholds. Methods: We conducted a prospective, observational multicenter study among participants receiving standardized MDR -TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration -time curve from 0 to 24 h, AUC0-24 h ) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. Results: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF > 450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART -derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg h/l (bedaquiline M2); 49.3 mg h/l (moxifloxacin); 119.3 mg h/l (linezolid); 718.7 mg h/l (cycloserine). Conclusions: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR -TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs. ; Funding Agencies|National Natural Science Foundation of China, Fudan University, Shanghai Health Committee [20190229]; Heart and Lung Foundation [SLS 20181256]; Stockholm County Council [2019-05 901]; Swedish Research Council [2019-05 912, FORSS-964535]; Research Council of south-eastern Sweden; [GWVI-11.1-05]; [81874273]