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Antimicrobial Agents and Chemotherapy, July 2007, p. 2546-2551, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01550-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis Patients

Rovina Ruslami,^1, Hanneke M. J. Nijland,^2, Bachti Alisjahbana,³ Ida Parwati,⁴ Reinout van Crevel,⁵ and Rob E. Aarnoutse^2*

Department of Pharmacology, Medical Faculty, University of Padjadjaran, Bandung, Indonesia,¹ Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands,² Department of Internal Medicine, Medical Faculty, University of Padjadjaran, Hasan Sadikin Hospital, Bandung, Indonesia,³ Department of Clinical Pathology, Medical Faculty, University of Padjadjaran, Hasan Sadikin Hospital, Bandung, Indonesia,⁴ Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands⁵

Received 13 December 2006/ Returned for modification 9 January 2007/ Accepted 12 April 2007

Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration-time curve from 0 to 24 h [AUC_0-24]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg·h/liter) compared to the standard-dose group (48.5 mg·h/liter). Maximum rifampin concentrations (C_max) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin C_max was 8 mg/liter was 96% versus 79% (P = 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P = 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC_0-24 and C_max of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.

Published ahead of print on 23 April 2007.

The first two authors contributed equally to this study and share first authorship.

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