Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline

Lénaïg Tanneau, Mats O Karlsson, Andreas H Diacon, Justin Shenje, Jorge De Los Rios, Lubbe Wiesner, Caryn M Upton, Kelly E Dooley, Gary Maartens, Elin M Svensson, Lénaïg Tanneau, Mats O Karlsson, Andreas H Diacon, Justin Shenje, Jorge De Los Rios, Lubbe Wiesner, Caryn M Upton, Kelly E Dooley, Gary Maartens, Elin M Svensson

Abstract

Background and objective: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and 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 coadministered.

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 were 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, while the PK of DM-6705 metabolite were 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 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV).

Conclusions: This is the first 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 coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

Trial registration: ClinicalTrials.gov NCT02583048.

Conflict of interest statement

LT, MOK, AHD, JS, JDLR, LW, CMU, KED, GM, and EMS have no conflicts of interest to declare.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Observed delamanid and DM-6705 concentrations over the study period
Fig. 2
Fig. 2
Visual predictive checks of the final model for both delamanid and DM-6705 concentrations, for the sparse sampling occasions only (a) and stratified by the three rich sampling occasions (b). The solid and dashed lines represent the median, and 2.5th and 97.5th percentiles of the observed data (black circles), respectively, and the shaded areas represent the simulation-based 95% confidence intervals for the corresponding percentiles. Dashed vertical lines represent the time of dosing

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