TY - JOUR
T1 - Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment
AU - Koele, Simon E.
AU - Van Beek, Stijn W.
AU - Maartens, Gary
AU - Brust, James C.M.
AU - Svensson, Elin M.
N1 - Funding Information:
G.M. is supported in part by core funding for the Wellcome Centre for Infectious Diseases Research in Africa [203135/Z/16/Z]. J.C.M.B. is supported by the U.S. National Institutes of Health (NIH) R01AI114304, R01AI145679, and K24AI155045 and the Einstein-Rockefeller-CUNY CFAR P30AI124414. E.M.S. is supported by PanACEA, which is part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 2 program supported by the European Union (grant number TRIA2015-1102-PanACEA). We have no conflict of interest to declare.
Publisher Copyright:
© 2022 American Society for Microbiology. All rights reserved.
PY - 2022/3
Y1 - 2022/3
N2 - Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with 216.4% to 259.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.
AB - Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption. A model-based simulation study was performed. Pharmacokinetic profiles of bedaquiline and its metabolite M2 (associated with QT prolongation) were simulated for 5,000 virtual patients for different durations and starting points of treatment interruption. Weekly bedaquiline area under the concentration-time curve (AUC) and M2 maximum concentration (Cmax) deviation before interruption and after reloading were assessed to evaluate the efficacy and safety, respectively, of the reloading strategies. Bedaquiline weekly AUC and M2 Cmax deviation were mainly driven by the duration of interruption and only marginally by the starting point of interruption. For interruptions with a duration shorter than 2 weeks, no new loading dose is needed. For interruptions with durations between 2 weeks and 1 month, 1 month and 1 year, and longer than 1 year, reloading periods of 3 days, 1 week, and 2 weeks, respectively, are recommended. This reloading strategy results in an average bedaquiline AUC deviation of 1.88% to 5.98% compared with 216.4% to 259.8% without reloading for interruptions of 2 weeks and 1 year, respectively, without increasing M2 Cmax. This study presents easy-to-implement reloading strategies for restarting a patient on bedaquiline treatment after an interruption.
KW - Mycobacterium tuberculosis
KW - bedaquiline
KW - pharmacokinetics
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U2 - 10.1128/aac.01749-21
DO - 10.1128/aac.01749-21
M3 - Article
C2 - 35007141
AN - SCOPUS:85126651245
SN - 0066-4804
VL - 66
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 3
M1 - e01749-21
ER -
