Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens

Abstract

Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.

Linezolid and the risk of QT interval prolongation: A pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System

“…In the present study, we found that LZD was usually combined with >3 drugs (such as bedaquiline, clofazimine and delamanid) according to the reporting system (see Table 4 for details). There is a large body of evidence that bedaquiline, delamanid and fluoroquinolones can cause QTp 16,19–21 . Therefore, the results obtained in this study may have been influenced by these drugs to some extent, exaggerating the role of LZD in the development QTp.…”

“…There is a large body of evidence that bedaquiline, delamanid and fluoroquinolones can cause QTp. 16,[19][20][21] Therefore, the results obtained in this study may have been influenced by these drugs to some extent, exaggerating the role of LZD in the development QTp.…”

Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling

“…Bedaquiline and its primary metabolite M2 exposures at the current standard dosing regimen (400 mg once daily for 14 days followed by 200 mg three times weekly) have the potential for safety concerns related to QTc interval prolongation and hepatic adverse events [ 10 – 12 ]. Alternative once-daily dosing (200 mg once daily for 8 weeks followed by 100 mg once daily) of bedaquiline is of interest to increase patient adherence to obtain optimal efficacy [ 12 ]. Pretomanid has overall acceptable clinical safety profiles; however, pretomanid combined with bedaquiline and linezolid can have additive effects, leading to an increased potential of certain adverse effects [ 13 ].…”

Model‐based dose optimization framework for bedaquiline, pretomanid and linezolid for the treatment of drug‐resistant tuberculosis

“…Therefore, alternative bedaquiline dosing, 200 mg QD for 9 weeks followed by 100 mg QD, has been proposed. Prior analyses predicted comparable safety concerns associated with alternative bedaquiline dosing and approved dosing 35 . Our simulations suggested a minor difference in Mtb clearance following bedaquiline QD dosing compared to the approved dosing.…”

“…Prior analyses predicted comparable safety concerns associated with alternative bedaquiline dosing and approved dosing. 35 Our simulations suggested a minor difference in Mtb clearance following bedaquiline QD dosing compared to the approved dosing. Linezolid has been a key drug in more than five drug combination regimens and was widely used for the treatment of MDR-TB before the availability of bedaquiline and pretomanid.…”