PMID- 38176643 OWN - NLM STAT- MEDLINE DCOM- 20240224 LR - 20240224 IS - 1878-3511 (Electronic) IS - 1201-9712 (Linking) VI - 140 DP - 2024 Mar TI - Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment. PG - 62-69 LID - S1201-9712(24)00001-8 [pii] LID - 10.1016/j.ijid.2024.01.001 [doi] AB - 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, AUC(0-24 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 AUC(0-24 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. CI - Copyright (c) 2024. Published by Elsevier Ltd. FAU - Wang, Sainan AU - Wang S AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Forsman, Lina Davies AU - Forsman LD AD - Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Division of Infectious Diseases, Karolinska Institutet Solna, Stockholm, Sweden. FAU - Xu, Chunhua AU - Xu C AD - Fengxian District Center for Disease Control and Prevention, Shanghai, China. FAU - Zhang, Haoyue AU - Zhang H AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Zhu, Yue AU - Zhu Y AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Shao, Ge AU - Shao G AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Wang, Shanshan AU - Wang S AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Cao, Jiayi AU - Cao J AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Xiong, Haiyan AU - Xiong H AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. FAU - Niward, Katarina AU - Niward K AD - Department of Infectious Diseases in Ostergotland, Region Ostergotland and Institution for Biomedical and Clinical Sciences, Linkoping University, Linkoping, Sweden. FAU - Schon, Thomas AU - Schon T AD - Department of Infectious Diseases in Ostergotland, Region Ostergotland and Institution for Biomedical and Clinical Sciences, Linkoping University, Linkoping, Sweden; Department of Infectious Diseases, Kalmar County Hospital, Kalmar, Linkoping University, Sweden. FAU - Bruchfeld, Judith AU - Bruchfeld J AD - Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Division of Infectious Diseases, Karolinska Institutet Solna, Stockholm, Sweden. FAU - Zhu, Limei AU - Zhu L AD - Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China. FAU - Alffenaar, Jan-Willem AU - Alffenaar JW AD - University of Sydney, Faculty of Medicine and Health, School of Pharmacy, Sydney, Australia; Westmead Hospital, Sydney, Australia; Sydney Institute for Infectious Diseases, University of Sydney, Sydney, Australia. FAU - Hu, Yi AU - Hu Y AD - Department of Epidemiology, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China. Electronic address: yhu@fudan.edu.cn. LA - eng PT - Journal Article PT - Multicenter Study PT - Observational Study DEP - 20240103 PL - Canada TA - Int J Infect Dis JT - International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases JID - 9610933 RN - 0 (Antitubercular Agents) RN - 95IK5KI84Z (Cycloserine) RN - 0 (Diarylquinolines) RN - ISQ9I6J12J (Linezolid) RN - U188XYD42P (Moxifloxacin) SB - IM MH - Humans MH - *Antitubercular Agents/adverse effects/pharmacokinetics MH - Cycloserine/adverse effects MH - Diarylquinolines/therapeutic use MH - Linezolid/adverse effects MH - Moxifloxacin/therapeutic use MH - Prospective Studies MH - *Tuberculosis, Multidrug-Resistant/drug therapy OTO - NOTNLM OT - Drug exposure OT - Multidrug-resistant tuberculosis OT - Side effects OT - Threshold EDAT- 2024/01/05 00:43 MHDA- 2024/02/23 06:42 CRDT- 2024/01/04 19:15 PHST- 2023/10/26 00:00 [received] PHST- 2023/12/29 00:00 [revised] PHST- 2024/01/02 00:00 [accepted] PHST- 2024/02/23 06:42 [medline] PHST- 2024/01/05 00:43 [pubmed] PHST- 2024/01/04 19:15 [entrez] AID - S1201-9712(24)00001-8 [pii] AID - 10.1016/j.ijid.2024.01.001 [doi] PST - ppublish SO - Int J Infect Dis. 2024 Mar;140:62-69. doi: 10.1016/j.ijid.2024.01.001. Epub 2024 Jan 3.