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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{triangledown}

Rovina Ruslami,1,{dagger} Hanneke M. J. Nijland,2,{dagger} Bachti Alisjahbana,3 Ida Parwati,4 Reinout van Crevel,5 and Rob E. Aarnoutse2*

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 [AUC0-24]) 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 (Cmax) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin Cmax 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 AUC0-24 and Cmax 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Phone: 31 24 3616405. Fax: 31 24 3668755. E-mail: R.Aarnoutse{at}akf.umcn.nl

{triangledown} Published ahead of print on 23 April 2007.

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

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.



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