Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the modelpredicted upper bounds of the 90% confidence intervals of Delta QTc values were <10 ms at the simulated maximum concentration (C-max) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDRTB who receive delamanid.

Automated summary

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of delamanid and its major metabolite DM-6705 in pediatric participants with MDR-TB. The analysis revealed a transit model with three compartments for delamanid absorption and two-compartment models with linear elimination for the dispositions of delamanid and DM-6705. The model included covariates such as body weight, age, formulation, and dose. Simulations were performed to calculate appropriate doses for different age/weight groups. Concentration-QTc analysis showed a significant positive correlation between DM-6705 concentrations and QTcB values, but the effect on QT interval following the proposed dosing was unlikely to be clinically meaningful.