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

Abstract

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'...

Daily Rifapentine for Treatment of Pulmonary Tuberculosis. A Randomized, Dose-Ranging Trial

“…Interindividual variability in rifapentine pharmacokinetics is substantial, particularly with mg/kg, because weight does not significantly impact rifapentine clearance (27). In our trial, overlap of Definition of abbreviations: CI = confidence interval by Wilson score method; SAE = serious adverse event.…”

“…Plasma concentrations of rifapentine were determined by a validated high-pressure liquid chromatography method in a single laboratory (26). Population pharmacokinetic models were developed using nonlinear mixed effects modeling (NONMEM, version 7; ICON plc, Dublin, Ireland) (27,28). Post hoc Bayesian estimates of individual areas under the concentration-time curve (AUC) were derived from the models.…”

Novel Dosing Strategies Increase Exposures of the Potent Antituberculosis Drug Rifapentine but Are Poorly Tolerated in Healthy Volunteers

“…The difference in exposures in our study compared with those in TBTC study 29X may be due to differences in participants' weights. Weight does not significantly impact RPT oral clearance (17), which means that higher-weight individuals (such as the healthy volunteers in our trial) receive higher doses (in milligrams) and have higher exposures than lower-weight individuals (such as patients with TB) for the same milligram-per-kilogram dose (the median dose in TBTC study 29X was 900 mg; in ACTG study A5311 it was 1,350 mg). In addition, in our study the intention was to increase exposures by dividing the dose or giving the dose with a meal type known to enhance absorption (11).…”

“…For rifampin, increasing the dose results in supraproportional increases in plasma drug concentrations (4). In contrast, RPT bioavailability decreases with increasing dose (17), so alternative strategies to increase exposures are needed. To maximize the likelihood of success with RPT-containing shorter-duration regimens, the relationships between exposure and microbiologic response must be better understood and fully characterized.…”

“…The population PK model was developed using nonlinear mixed effect modeling, implemented in NONMEM software. Previously described model structure and model-building procedures were used (17). In brief, parent and metabolite data were fitted simultaneously.…”