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

Abstract

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.

Addressing bedaquiline treatment interruptions in the treatment of drug-resistant TB

“…We observed consistency in that interruptions of ≤4 weeks after week 1 of BDQ treatment require completion of a 1-week BDQ 400 mg QD loading dose, and that interruptions <2 weeks following 4–16 weeks BDQ exposure only require restarting with maintenance phase dosing. 15 , 16 For treatment interruptions ≤2 months following 2–36 weeks of prior BDQ exposure during the maintenance phase, our analysis provides more detailed recommendations by simulating scenarios for re-initiating with BDQ maintenance dosing (in some cases necessitating reloading for 1 week), rather than just evaluating re-starting with a 400 mg QD reloading dose in all scenarios.…”

Quantitative approaches to drug safety: The 2022 PSP special issue

“…The latter drug is a chemotherapeutic that can sometimes cause hand‐foot syndrome, a form of dermatitis, and the authors explore how concurrent treatment with TAS‐114 may improve tolerance of capecitabine in some patients. Similarly, Keutzer et al 8 use PopPK modeling to examine bedaquiline, a drug with a long terminal half‐life that is used for treatment of drug‐resistant tuberculosis. When bedaquiline is reintroduced after dose interruption, concerns exist about the risk of QT‐prolongation and potential ventricular arrhythmias, and the results presented by the authors demonstrate a potential strategy for safe reintroduction of the drug.…”