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Pharmacokinetics, tolerability, and bacteriological response of rifampin administered at 600, 900, and 1,200 milligrams daily in patients with pulmonary tuberculosis

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Author(s)

R. E. Aarnoutse, G. S. Kibiki, K. Reither, H. H. Semvua, F. Haraka, C. M. Mtabho, S. G. Mpagama, J. van den Boogaard, I. M. Sumari-de Boer, C. Magis-Escurra, M. Wattenberg, J. G.M. Logger, L. H.M. te Brake, M. Hoelscher, S. H. Gillespie, A. Colbers, P. P. J. Phillips, G. Plemper van Balen, M. J. Boeree, PanACEA Consortium

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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.).

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Original languageEnglish
Article numbere01054-17
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number11
DOIs
StatePublished - 1 Nov 2017

    Research areas

  • Drug safety, Pharmacokinetics, Rifampin, Tuberculosis

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