Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis

Abstract

Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and whether it can be used together with rifamycins, which are key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, and pyrazinamide plus either rifampin or rifabutin versus standard of care under fed conditions, and the AIDS Clinical Trials Group 5306 (A5306) trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reductions in pretomanid AUC (area under the concentration-time curve) compared to those taking rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in the APT and A5306 trials, respectively. Median maximum concentrations (Cmax) in the rifampin and rifabutin arms were 2.14 and 3.35 mg/liter, while median AUC0-24 values were 30.1 and 59.5 mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin. (This study has been registered at ClinicalTrials.gov under identifier NCT02256696.).

Keywords: Mycobacterium tuberculosis; pharmacokinetic; pharmacokinetics; pretomanid; rifabutin; rifampin; tuberculosis.

Copyright © 2021 American Society for Microbiology.

Figures

FIG 1

Visual predictive check for pretomanid concentration (in milligrams per liter) versus time (time since observed dose), stratified by study and treatment arms. Circles represent original data, dashed and solid lines are the 5th, 50th, and 95th percentiles of the original data, and the shaded areas are the corresponding 95% confidence intervals for the same percentiles, as predicted by the model. Vertical yellow lines on the x axis represent bins for sampling time points. An appropriate model is expected to have most observed percentiles within the simulated confidence intervals.

FIG 2

Box-and-whisker plots showing individual model-predicted pretomanid AUC0–24 and Cmax on day 14 in the APT study, stratified by treatment arm. The dots represent individual values, the box is the interquartile range (IQR), and the whiskers show 2.5th and 97.5th percentiles. Data were available for 57 patients at day 14.

FIG 3

Probability of target attainment (PTA) versus MIC, assuming 15% protein binding in each treatment arm at steady state. A 1-log10 killing (48% fT>MIC) represents the PK/pharmacodynamic (PK/PD) target of bactericidal activity, while a 1.59-log10 (77% fT>MIC) PK/PD target represents 80% of maximum observed killing. Calculations were based on 10,000 simulations of the median TB patient PK observed in the APT study.