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Background: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis. Delamanid is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when co-administered. 

Methods: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.

Results: Delamanid PK was described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h (95% confidence interval 0.501–2.20)) and linear elimination. The PK of DM-6705 metabolite, was described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 hours and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline co-administration did not affect delamanid PK. Other than allometric scaling with body weight, no patients’ demographics were significant (including HIV). 

Conclusions: This is the first published joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline co-administration, and HIV co-infection (dolutegravir co-administration) did not have an effect on delamanid and DM-6705 PK.

Aims: To externally validate an earlier characterized relationship between bedaquiline exposure and decline in bacterial load in a more difficult-to-treat patient population, and to explore the performances of alternative dosing regimens through simulations.

Methods: The bedaquiline exposure-response relationship was validated using time-to-positivity data from 233 newly diagnosed or treatment-experienced patients with drug-resistant tuberculosis from the C209 open-label study. The significance of the exposure-response relationship on the bacterial clearance was compared to a constant drug effect model. Tuberculosis resistance type and the presence and duration of antituberculosis pre-treatment were evaluated as additional covariates. Alternative dosing regimens were simulated for tuberculosis patients with different types of drug resistance.

Results: High bedaquiline concentrations were confirmed to be associated with faster bacterial load decline in patients, given that the exposure-effect relationship provided a significantly better fit than the constant drug effect (relative likelihood = 0.0003). The half-life of bacterial clearance was identified to be 22% longer in patients with pre-extensively drug-resistant (pre-XDR) tuberculosis (TB) and 86% longer in patients with extensively drug-resistant (XDR) TB, compared to patients with multidrug-resistant (MDR) TB. Achievement of the same treatment response for (pre-)XDR TB patients as for MDR TB patients would be possible by adjusting the dose and dosing frequency. Furthermore, daily bedaquiline administration as in the ZeNix regimen, was predicted to be as effective as the approved regimen.

Conclusion: The confirmed bedaquiline exposure-response relationship offers the possibility to predict efficacy under alternative dosing regimens, and provides a useful tool for potential treatment optimization.

Bedaquiline (BDQ) has shown great value in the treatment of multidrug-resistant tuberculosis (MDR-TB) in recent years. However, exposure–safety relationships must be explored to extend the use of BDQ. Two reported safety findings for BDQ are prolongation of the QTc interval and elevation of transaminase levels. In this study, we investigated the potential relationships between BDQ and/or its main metabolite (M2) pharmacokinetic (PK) metrics and QTcF interval or transaminase levels in patients with MDR-TB using the approved dose regimen. Data from 429 patients with MDR-TB from two phase IIb studies were analyzed via nonlinear mixed-effects modeling. Individual model-predicted concentrations and summary PK metrics were evaluated, respectively, in the QTcF interval and transaminase level exposure–response models. Investigation of further covariate effects was performed in both models. M2 concentrations were found to be responsible for the drug-related QTcF increase in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics. Simulations with the final model suggested that doses higher than the approved dose (leading to increased M2 concentrations) are not expected to lead to a critical QTcF interval increase. No exposure–safety relationship could be described with transaminase levels despite previous reports of higher levels in patients treated with BDQ. The developed longitudinal models characterized the role of M2 concentrations in QTc interval prolongation and found no concentration dependency for transaminase level elevation, together suggesting that BDQ exposure at the high end of the observed range may not be associated with a higher risk of safety events.

Bedaquiline and delamanid are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with QTc prolongation. We aimed to investigate the relationships between the drugs’ plasma concentrations and observed QTcF prolongation 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 bedaquiline , delamanid or bedaquiline+delamanid. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under co-administration, 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% (95CI 22%-40%) for M2 and 33% (95CI 24%-54%) for DM-6705. The generated combined effect was not greater but close to “additivity” in the analysed concentration range. Predictions with the final model suggested a similar QT prolonging potential with novel simplified regimens with novel once daily dosing compared to the approved regimens, with a maximum median change from baseline QTcF increase of 20 ms 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, and predictions from the model support the use of these drugs together in once daily regimens.