Title
Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline
Date Issued
01 August 2022
Access level
open access
Resource Type
journal article
Author(s)
Tanneau L.
Karlsson M.O.
Diacon A.H.
Shenje J.
Wiesner L.
Upton C.M.
Dooley K.E.
Maartens G.
Svensson E.M.
Publisher(s)
Adis
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.
Start page
1177
End page
1185
Volume
61
Issue
8
Language
English
OCDE Knowledge area
Sistema respiratorio
Enfermedades infecciosas
Scopus EID
2-s2.0-85131529623
PubMed ID
Source
Clinical Pharmacokinetics
ISSN of the container
03125963
Sponsor(s)
This analysis was funded by the Division of AIDS at the National Institutes of Health (NIH). The University of Cape Town Clinical PK Laboratory is supported in part via the Adult Clinical Trial Group (ACTG), by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701. KED is supported by K24AI150349 from the NIAID, NIH.
Sources of information:
Directorio de Producción Científica
Scopus