title: 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.).
authors.affiliation: UCSF School of Pharmacy, Bioengineering and Therapeutic Sciences, San Francisco, California, USA Rada.Savic@ucsf.edu.
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Centers for Disease Control and Prevention, Division of Tuberculosis Elimination, Atlanta, Georgia, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Bliven-Sizemore
authors.affiliation: University of Texas Health Science Center and VAMC, San Antonio, Texas, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Denver Public Health, Denver, Colorado, USA.
authors.forename: William
authors.initials: W
authors.lastname: Burman
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics*; D001682:Biological Availability; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D012293:Rifampin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013997:Time Factors; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin; C018421:rifapentine