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Antimicrobial Agents and Chemotherapy, June 2008, p. 2138-2148, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.00461-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Rifampin in Pulmonary Tuberculosis Patients, Including a Semimechanistic Model To Describe Variable Absorption {triangledown}

Justin J. Wilkins,1,2 Radojka M. Savic,2 Mats O. Karlsson,2 Grant Langdon,1,2 Helen McIlleron,1* Goonaseelan Pillai,3 Peter J. Smith,1 and Ulrika S. H. Simonsson2

Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa,1 Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden,2 Modeling & Simulation, Clinical Development & Medical Affairs, Novartis Pharmaceuticals AG, Basel, Switzerland3

Received 3 April 2007/ Returned for modification 10 June 2007/ Accepted 31 March 2008

This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to 600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 liters·h–1, while the volume of distribution was estimated to be 53.2 liters. Interindividual variability was estimated to be 52.8% for clearance and 43.4% for volume of distribution. Interoccasional variability was estimated for CL/F (22.5%) and mean transit time during absorption (67.9%). The use of single-drug formulations was found to increase both the mean transit time (by 104%) and clearance (by 23.6%) relative to fixed-dose-combination use. A strong correlation between clearance and volume of distribution suggested substantial variability in bioavailability, which could have clinical implications, given the dependence of treatment effectiveness on exposure. The final model successfully described rifampin pharmacokinetics in the population studied and is suitable for simulation in this context.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, K45 Old Main Building, Groote Schuur Hospital, Observatory 7925, South Africa. Phone: 27 21 406 6292. Fax: 27 21 448 1989. E-mail: Helen.McIlleron{at}uct.ac.za

{triangledown} Published ahead of print on 7 April 2008.

Antimicrobial Agents and Chemotherapy, June 2008, p. 2138-2148, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.00461-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Goutelle, S., Bourguignon, L., Maire, P. H., Van Guilder, M., Conte, J. E. Jr., Jelliffe, R. W. (2009). Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs. Antimicrob. Agents Chemother. 53: 2974-2981 [Abstract] [Full Text]  


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