A modeling-based proposal for safe and efficacious reintroduction of bedaquiline after dose interruption: A population pharmacokinetics study

CPT Pharmacometrics Syst Pharmacol. 2022 May;11(5):628-639. doi: 10.1002/psp4.12768. Epub 2022 Feb 16.


Bedaquiline (BDQ) is recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) for the majority of patients. Given its long terminal half-life and safety concerns, such as QTc-prolongation, re-introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation-based study, we investigated different loading dose strategies for BDQ re-introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re-introduction, including no loading dose, 1- and 2-week loading doses (200 mg and 400 mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR-TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc-prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6 weeks) require a 2-week loading dose of 200 mg once daily in the typical patient. If treatment was interrupted for longer than 8 weeks, a 2-week loading dose (400 mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re-introduction providing guidance to clinicians for safe and efficacious BDQ dosing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents
  • Diarylquinolines / pharmacokinetics
  • Humans
  • Long QT Syndrome*
  • Tuberculosis, Multidrug-Resistant* / drug therapy


  • Antitubercular Agents
  • Diarylquinolines
  • bedaquiline