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

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01133-2.

Factors Associated with Unsuccessful Treatment of Bedaquiline and or Delamanid Based Regimens in Multidrug-Resistant Tuberculosis: A Review

“…In addition, dysregulation of CD8 T cells, overactivation of mTORC1 signaling, and decreased levels of GSH, impair of autophagy and mitophagy processes which impact decreasing M.Tb microbial clearance in elderly. (Bonavida et al, 2022) Interestingly, the absorption of bedaquiline and delamanid was not affected by age, and concomitant use of delamanid with bedaquiline had no impact on the pharmacokinetic profile delamanid and its metabolite, DM-6705 (Tanneau et al, 2022).…”

Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis

“…12 A mixed-effect pharmacokinetic modeling study reported that albumin concentrations, HIV coinfection, or bedaquiline coadministration did not have an effect on delamanid pharmacokinetics. 21 This is the first study assessing the plasma levels of bedaquiline and delamanid in a cohort of patients with pre-XDR TB in India. One limitation of the study is its small sample size that limits any conclusions regarding an association between drug exposure and treatment outcomes.…”

“… 12 A mixed-effect pharmacokinetic modeling study reported that albumin concentrations, HIV co-infection, or bedaquiline coadministration did not have an effect on delamanid pharmacokinetics. 21 …”

Advances of new drugs bedaquiline and delamanid in the treatment of multi-drug resistant tuberculosis in children

“…Plasma albumin concentration had no discernible effect on delamanid metabolism. Delamanid PK was not affected by the co-administration of bedaquiline (Tanneau et al, 2022). Using a large body of delamanid clinical data, a PK model for delamanid was developed in individuals with pulmonary MDR-TB.…”