Therapeutic Drug Monitoring-Based Efficacy and Safety of Bedaquiline in Chinese Multidrug-Resistant Tuberculosis

Background: Bedaquiline was approved by the US Food and Drug Administration (FDA) for the treatment of drug-resistant tuberculosis in 2012, and significantly improved multidrug-resistant tuberculosis (MDR-TB) patients treatment outcomes. However, data of the efficacy, safety of bedaquiline for the Chinese tuberculosis patients were still lacked, and the plasma concentration of bedaquiline during the treatment and its elimination after treatment discontinuation also had not yet be elucidated. In this study, we demonstrated the efficacy and safety of bedaquiline for the treatment of MDR-TB or XDR-TB patients based on the therapeutic drug monitoring. Methods: 35 patients who started on bedaquiline for drug-resistant tuberculosis were identified. We extracted the patient's medical record information based on their informed consent, and established a standardized monitoring system to track outcomes of patients started on bedaquiline for MDR-TB. The plasma concentration of bedaquiline were determined by ultra-performance liquid chromatography combined with tandem mass spectrometry. Findings: After the 24 weeks bedaquiline treatment, 80% of these patients’ sputum culture conversed negative, and the median time to culture conversion was 75.5 (IQR 52-126) days. 21 (21/26, 80.8%) patients were eventually cured, 2 (2/26, 7.7%) patients failed. The most frequently adverse events during the treatment included QTc prolongation (16/35, 45.7%), peripheral neuropathy (9/35, 25.7%), and gastrointestinal disturbances (8/35, 22.9%). During treatment, the median plasma bedaquiline were fluctuated around 0.6 µg/ml, and gradually decreased after bedaquiline discontinued, about 0.2 µg/ml of bedaquiline was still undegraded after bedaquiline withdrawal 13 months. Moreover, combination with clofazimine increased the possibility of QTc prolongation during the treatment of MDR-TB with bedaquiline, and the decreased serum potassium concentration was also a reason for the prolonged QTc induction with bedaquiline. Interpretation: This study highlighted the efficacy and safety of bedaquiline based on the plasma concentration monitoring, analyzed the reasons of bedaquiline induced QTc prolongation, which had not yet be elucidated before. Funding: This work was supported by the Hospital Pharmacy Special Project of Zhejiang Pharmaceutical Society (2018ZYY31, 2019ZYY27, 2020ZYY08), Zhejiang Medical and Health Science and Technology Plan (2015PYA008, 2020KY741) and Zhejiang Provincial Natural Science Foundation of China under Grant (LYY18H300001), Medical promising youngster of Hangzhou.Declaration of Interests: The authors declare no conflict of interest.Ethics Approval Statement: This study was approved by the Ethic Committee of Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine.