Antimicrobial Agents and Chemotherapy, November 2005, p. 4429-4436, Vol. 49, No. 11
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.11.4429-4436.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetics of Rifapentine and Its Primary Desacetyl Metabolite in South African Tuberculosis Patients
Grant Langdon,1,2 Justin Wilkins,1,2 Lynn McFadyen,3 Helen McIlleron,1* Peter Smith,1 and Ulrika S. H. Simonsson2Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa,1 Division of Pharmacokinetics and Drug Therapy, Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden,2 Clinical Research and Development, Pfizer, Sandwich, United Kingdom3
Received 27 June 2005/ Returned for modification 27 July 2005/ Accepted 5 August 2005
This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.
* Corresponding author. Mailing address: Division of Clinical Pharmacology, Groote Schuur Hospital, Observatory 7700, Cape Town, South Africa. Phone: (27) 21 406 6292. Fax: (27) 21 448 1989. E-mail: hmciller{at}uctgsh1.uct.ac.za.
Antimicrobial Agents and Chemotherapy, November 2005, p. 4429-4436, Vol. 49, No. 11
0066-4804/05/$08.00+0 doi:10.1128/AAC.49.11.4429-4436.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
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