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Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB

Aarnoutse, R. E. and Kibiki, G. S. and Reither, K. and Semvua, H. H. and Haraka, F. and Mtabho, C. M. and Mpagama, S. G. and van den Boogaard, J. and Sumari-de Boer, I. M. and Magis-Escurra, C. and Wattenberg, M. and Logger, J. G. M. and Te Brake, L. H. M. and Hoelscher, M. and Gillespie, S. H. and Colbers, A. and Phillips, P. P. J. and Plemper van Balen, G. and Boeree, M. J.. (2017) Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB. Antimicrobial agents and chemotherapy, 61 (11). e01054-17.

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Official URL: http://edoc.unibas.ch/57488/

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Abstract

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Medicine > Clinical Research (Reither)
UniBasel Contributors:Reither, Klaus
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:21 Dec 2017 12:29
Deposited On:21 Dec 2017 12:29

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