Population Pharmacokinetics of Rifapentine and Its Primary Desacetyl Metabolite in South African Tuberculosis Patients

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Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.Rifapentine (RFP), a cyclopentyl rifamycin, is an orally administered drug registered by the Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis (TB). It exerts its antibacterial activity through inhibition of DNAdependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (32). RFP has a microbiologically active metabolite, 25-desacetyl rifapentine (25-DRFP) (10). RFP has a long half-life (5, 17) and superior in vitro potency against M. tuberculosis in comparison with rifampin and rifabutin (10), making it an attractive candidate for shortening and simplifying antitubercular therapy.Currently, RFP is dosed at 600 mg either once weekly or twice weekly in human immunodeficiency virus (HIV)-negative patients with noncavitary TB (2). There is concern that the development of acquired rifamycin monoresistance (ARR), treatment failure, and relapse may be associated with intermittent dosing (4, 20), insufficient companion drug exposure (33), or low rifamycin concentrations (9, 21). RFP's sterilizing effect has been shown to be dose dependent in murine studies which suggest that daily doses of RFP may reduce treatment duration to just 3 months (25,26,37), and higher doses of RFP are associated with improved early bactericidal activity in humans (29). Clinical trials are currently evaluating new antituberculosis regimens containing higher doses of RFP used intermittently or daily doses of RFP. Concomitant food has a marked effect on RFP absorption (6). The effect of food on systemic RFP exposure may therefore impact treatment activity and safety. The aim of this study was to investigate the effect of meals differing in fat and bulk content on the rate and extent of RFP absorption and 25-DRFP disposition. The ...

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 84%

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confidence: 99%

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Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers

Zvada

Walt

Smith

et al. 2010

Self Cite

“…Our clinical trial simulations suggest that dose splitting and administration of drug with high-fat food can be utilized as effective strategies to optimally achieve PK-pharmacodynamic targets, once they are firmly established. The population pharmacokinetics of single-dose RFP among patients with pulmonary TB disease have been described previously (24), and the effects of different food types on single-dose RFP exposures have also been evaluated using mathematical models (13). This analysis of single-dose and multiple-dose data from subjects receiving a broader range of RFP doses allowed exploration of the relationship between dose and bioavailability and the time and concentration dependency of clearance.…”

Section: Figmentioning

confidence: 99%

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

Savic

Bliven-Sizemore

et al. 2014

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h ؊1 , respectively, after a single dose to 2.2 and 5.0 liters · h ؊1 , respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) T uberculosis (TB) is a major global health problem and remains a leading cause of death from an infectious disease (1). The current first-line regimen for TB was developed decades ago, and 6 months of treatment is still required for cure (2). The long duration is challenging for patients and costly to TB programs. Rifapentine (RFP) is a cyclopentyl analogue of rifampin, the key sterilizing agent in the standard TB treatment regimen that kills bacteria by inhibiting DNA-dependent RNA polymerase. RFP has higher antimicrobial potency and a longer half-life than rifampin and was approved by the Food and Drug Administration (FDA) for treatment of TB at a dose of 600 mg twice weekly (in the intensive phase) and once weekly (in the continuation phase) (3). However, the relapse rate among patients in some patient populations treated with such an intermittent RFP regimen is unacceptably high, indicating that the optimal dosing regimen of RFP for TB treatment has yet to be fully characterized. Recent studies in a well-validated mouse model of TB disease have shown that the replacement of rifampin with RFP can shorten the treatment duration to 3 months or less when RFP is given daily and that RFP'...

“…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)(6)(7)(8)(9)(10)(11)(12)(13)(14)(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.…”

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confidence: 99%

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

Zurlinden

Eppers

Reisfeld

2016

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...