Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis

Q: What is the clinical evidence from this study?

Population: Drug-susceptible pulmonary tuberculosis (DS-TB) (n=105). Intervention: Bedaquiline, pretomanid, and clofazimine vs. Pyrazinamide only or standard anti-TB treatment (HRZE). Primary outcome: Maximum QTc interval prolongation (Emax) in a competitive interaction model (Emax 44.5 ms, 95% CI 38.3-53.5).

Q: What does this research mean for the field?

The combined use of bedaquiline, pretomanid, and clofazimine can lead to a maximum QT interval increase of 44.5 ms in patients with tuberculosis, with significant risk factors identified for QT prolongation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Mahmoud Tareq Abdelwahab; Elin M. Svensson; Andreas H. Diacon; Almarie Conradie; Morounfolu Olugbosi; Rod Dawson; Gary Maartens; Paolo Denti

doi:10.1128/aac.01399-25

March 9, 2026Antimicrobial Agents and ChemotherapyOpen Access

Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis

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Key result

Combined bedaquiline, pretomanid, and clofazimine prolongs maximum QT by ~45 ms without exceeding 500 ms.

Emax 44.5 ms
95% CI 38.3-53.5
n=105

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Why the study?

Limited information was available on the combined cardiotoxicity and QT prolongation associated with bedaquiline, pretomanid, and clofazimine in drug-resistant tuberculosis regimens.

Does the combined exposure to bedaquiline, pretomanid, and clofazimine result in additive or competitive QT interval prolongation in adults with tuberculosis?

Key Points

Characterize the combined concentration-QTc interaction of bedaquiline, pretomanid, and clofazimine to predict cardiotoxicity across various treatment regimens and identify high-risk patients.
Developed a competitive-inhibition interaction pharmacokinetic-pharmacodynamic model using 2,062 ECG measurements (1,089 matched with plasma drug concentrations) from 105 adults in an early-bactericidal activity study of drug-susceptible tuberculosis.
Integrated circadian oscillations, secular treatment trends, and age covariates to simulate drug-induced QTcF changes across patient demographics and dosing schedules.
The competitive model estimated a maximum shared QTcF prolongation of 44.5 ms (95% CI, 38.3–53.5), with EC50 estimates of 0.57 mg/L (95% CI, 0.28–1.26) for BDQM2, 0.903 mg/L (95% CI, 0.563–1.61) for clofazimine, and 26.9 mg/L (95% CI, 15.2–51.2) for pretomanid.
Simulations in high-risk 70-year-old non-Black individuals predicted that 39.1% experienced a drug-induced QTcF increase >30 ms after the standard loading period, compared to 29.4% following a 400 mg daily bedaquiline regimen.
Reassuringly, 0% of simulated replicates exceeded a critical QTcF threshold of 500 ms, and less than 1% surpassed 480 ms or had a baseline increase >60 ms.

Structured PICO

Does the combined exposure to bedaquiline, pretomanid, and clofazimine result in additive or competitive QT interval prolongation in adults with tuberculosis?

P

Population

105 treatment-naive adults (median age 30, 38.1% female) with drug-susceptible pulmonary tuberculosis whose data from a 14-day early bactericidal activity study were used for PK-PD modeling.

I

Intervention

Bedaquiline (400 mg day 1, 300 mg day 2, 200 mg days 3-14), Clofazimine (300 mg for 3 days, 100 mg until day 14), and Pretomanid (200 mg daily for 14 days), either alone or in combination.

C

Comparator

Pyrazinamide only (PZA) or standard anti-TB treatment (HRZE) arms, and pre-treatment baseline data.

O

Outcome

Combined concentration-QTc effect (drug-induced QTcF prolongation) evaluated using a competitive interaction model.safety

Main Result

Effect estimate: Emax 44.5 ms (95% CI 38.3-53.5)

Co-administration of bedaquiline, pretomanid, and clofazimine results in competitive, non-additive QT interval prolongation, requiring careful ECG monitoring in high-risk patients but presenting low risk for absolute QTcF >500 ms.

Limitations

Observation period was limited to 28 days, preventing identification of potential tolerance or desensitization upon chronic drug treatment
Lack of a bedaquiline monotherapy arm to adequately assess the isolated QT effect of its metabolite BDQM2
Data alone did not support robust characterization of circadian rhythm, requiring the use of informative priors
Between-subject variability on the maximal effect (Emax) parameter was not identifiable in the dataset
The secular trend estimated in the analysis is associated with large uncertainty
Observation period limited to 28 days, precluding identification of tolerance/desensitization.
No data on bedaquiline monotherapy to adequately assess QT effect of BDQM2 alone.
Data alone did not support robust characterization of circadian rhythm, requiring weakly informative priors.
Between-subject variability on Emax was not identifiable.
Large uncertainty associated with the estimated secular trend.

Implication

May inform QT monitoring in multidrug TB regimens; extends interaction modeling but leaves open prospective validation.

Abstract

Drug resistance (DR) poses a critical challenge to global efforts to manage tuberculosis (TB). Limited information is available on the combined cardiotoxicity of bedaquiline (BDQ), pretomanid (Pa), and clofazimine (CFZ), key drugs in current DR-TB treatment regimens. All of those prolong the QT interval. We aimed to describe this interaction to predict possible toxicities with established and novel dosing regimens to identify patients at higher risk of QT prolongation. The data for this analysis were obtained from an early-bactericidal activity study in drug-susceptible-TB of several TB drugs. We developed a competitive interaction model to evaluate combined concentration-QTc effect of all three drugs. The model was developed using ECG-matched PK measurements (105 patients, 2,062 observations). The model identified a maximum QT increase by all three drugs of 44.5 ms with respective EC50 values for BDQ, Pa, and CFZ of 0.57, 0.903, and 26.9 mg/L. For patients aged 70 years with non-black ancestry, at risk of increased BDQ exposure, simulations showed that 39.1% had a drug-induced QT change >30 ms after the loading period; this was 29.4% for following BDQ 400 mg daily regimen (part of UNITE4TB program). Reassuringly, no simulations resulted in a QTcF >500 ms, and less than 1% exceeded 480 ms or a change from baseline of >60 ms. We present a joint concentration-QT model of BDQ, Pa, and CFZ. The competitive interaction model serves as a tool to predict possible combined exposure-induced QT prolongation of these drugs in different dosing regimen and identify patients at high risk of significant QT-prolongation.

Discussion

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Cite This Study

Abdelwahab et al. (2026) studied Drug-susceptible pulmonary tuberculosis (DS-TB) (n=105). Bedaquiline, pretomanid, and clofazimine vs. Pyrazinamide only or standard anti-TB treatment (HRZE) was evaluated on Maximum QTc interval prolongation (Emax) in a competitive interaction model (Emax 44.5 ms, 95% CI 38.3-53.5). A joint competitive interaction model of bedaquiline, pretomanid, and clofazimine identified a maximum QT increase of 44.5 ms, predicting that no patients would exceed an absolute QTcF of 500 ms.

synapsesocial.com/papers/69b2581996eeacc4fcec7560 https://doi.org/10.1128/aac.01399-25

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Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Exposure-QTc modeling of bedaquiline, pretomanid, and clofazimine in adults with tuberculosis

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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