Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans.
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 single- and 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.
Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, USA.
Todd J
TJ
Zurlinden
Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, USA.
Garrett J
GJ
Eppers
Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, USA School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado, USA brad.reisfeld@colostate.edu.
Brad
B
Reisfeld
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics / Q000494:pharmacology; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D051381:Rats; D012293:Rifampin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D012294:Rifamycins / Q000493:pharmacokinetics / Q000494:pharmacology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D012294:Rifamycins; D012293:Rifampin; C018421:rifapentine