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Antimicrobial Agents and Chemotherapy, April 2006, p. 1170-1177, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1170-1177.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

Helen McIlleron,1* Peter Wash,2,{dagger} André Burger,2 Jennifer Norman,1 Peter I. Folb,3 and Pete Smith1

Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa,1 Brewelskloof Hospital, Worcester, South Africa,2 Medical Research Council of South Africa, Tygerberg, South Africa3

Received 7 June 2005/ Returned for modification 21 August 2005/ Accepted 9 January 2006

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Old Main Building, Groote Schuur Hospital, Observatory 7925, South Africa. Phone: 27 21 4066292. Fax: 27 21 4481989. E-mail: hmciller{at}uctgsh1.uct.ac.za.

{dagger} Present address: Calgary, Alberta, Canada.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1170-1177, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1170-1177.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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