Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling

Abstract

Background and introduction: The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose.

Methods: Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods.

Results: A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively.

Conclusion: Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.

Conflict of interest statement

The authors declare that they have no competing interests. JN, AL, and FP are employees of TB Alliance, the organization developing pretomanid. ES is involved in development of multiple novel anti-tuberculosis compounds through the UNITE4TB consortium.

© 2022. The Author(s).

Figures

Fig. 1

Mean plasma concentrations versus time after dose per dose and formulation of pretomanid at fed condition. Treatment A, 200 mg marketed formulation; B, 200 mg dispersible tablet formulation; C, 50 mg dispersible tablet formulation; D, 10 mg dispersible tablet formulation

Fig. 2

Visual predictive checks of the final model on the CL-011 study data (fed conditions only) by formulations and doses from time after dose to 96 h. The concentrations are plotted on log scale. The open circles represent the observed samples. The solid and dashed black lines represent the 50th and 10th/90th percentiles of the observations in the data set. The red- and blue-colored areas represent the 95% model-predicted confidence intervals for the corresponding percentiles

Fig. 3

Histogram of the simulated population of the AUC0–last from 300 simulations, compared with the observed AUC (red vertical lines), under fed state in the CL-011 study. The distribution of simulated AUC is represented by the 2.5th, 50th, and 97.5th percentiles in grey lines