Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

Abstract

b Rifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several singleand repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety. R ifapentine (RPT) is a rifamycin-class antibiotic indicated for the treatment of pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis and in the treatment of latent TB infection in patients at high risk of progression to TB disease. RPT has a longer half-life, increased affinity to serum protein binding (1), and a lower MIC against M. tuberculosis than rifampin, which is currently used as part of several first-line TB treatment regimens (2, 3). Moreover, the primary metabolite for RPT, 25-desacetyl rifapentine (dRPT), has also been found to be active against M. tuberculosis, although at markedly lower MICs (1, 3, 4). Because of these characteristics, RPT has been the subject of a number of clinical pharmacology studies aimed at evaluating pharmacokinetics and developing effective therapies (5-15). Although data from these investigations are valuable in their own right, mathematical modeling offers a way to complement these studies, synthesize their disparate data, and provide the clinician an additional tool to characterize and predict the absorption, distribution, metabolism, and excretion (ADME) of RPT under dosing conditions of interest.One of the very few such mathematical models was developed by Savic et al. (16), who used a classical compartmental modeling approach to assess human population pharmacokinetics of both RPT and dRPT. This model described the absorption, metabolism, and clearance of these two species and accurately predicted their time cour...

Development of physiologically‐based pharmacokinetic models for standard of care and newer tuberculosis drugs

“…For nine of the compounds (bedaquiline, clofazimine, ethambutol, ethionamide, isoniazid, linezolid, pyrazinamide, rifampicin, and rifapentine), the constructed models provide additional performance verification or the ability to account for additional mechanistic functionality (e.g., to describe DDIs or to simulate lung concentrations). 7 , 28 , 29 , 30 , 31 , 32 , 33 , 34 For the other two compounds (cycloserine and kanamycin), the constructed PBPK models are the first to be published in the literature.…”

“…Although PBPK models have been published previously for rifapentine, 28 , 32 the current model allows both auto‐induction of arylacetamide deacetylase (AADAC; modeled using a surrogate enzyme) and induction of CYP 3A4 following administration of rifapentine to be simulated. The simulated DDIs between rifapentine and midazolam showed good agreement with the reported magnitude of interaction, 8 with a slight over prediction of the change in C max .…”

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

“…A PBPK model was developed to predict tissue exposures of rifapentine, particularly in the lung, for different dosage regimens and to identify doses that could potentially cause efficacy or safety issues. 174 A more complex lung model consisting of a number of compartments, including pulmonary capillary blood, lung tissue, ELF, and alveolar air, was developed to investigate the lung exposures of a range of anti-TB drugs. 175 Simulations of plasma and pulmonary concentrations of various drugs, including rifampin, isoniazid, and ethambutol, demonstrated reasonable recovery of observed exposures of each of the drugs in ELF, thus, providing confidence in a framework for predicting lung PKs of novel anti-TB drugs.…”

“…The penetration of TB treatments into tissues, specifically into the lung lesions observed with the disease, has been investigated using PBPK models. A PBPK model was developed to predict tissue exposures of rifapentine, particularly in the lung, for different dosage regimens and to identify doses that could potentially cause efficacy or safety issues 174 . A more complex lung model consisting of a number of compartments, including pulmonary capillary blood, lung tissue, ELF, and alveolar air, was developed to investigate the lung exposures of a range of anti‐TB drugs 175 .…”