Author(s):
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Aarnoutse, R.E.
;
Kibiki, G.S.
; Reither, K.; Semvua, H.H.; Haraka, F.; Mtabho, C.M.; Mpagama, S.G.;
Boogaard, J. van den
; Sumari-de Boer, I.M.;
Magis-Escurra, C.
; Wattenberg, M.; Logger, J.G.M.;
Brake, L.H.M. te
; Hoelscher, M.; Gillespie, S.H.;
Colbers, A.
; Phillips, P.P.; Plemper van Balen, G.;
Boeree, M.J.
|
Subject:
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Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
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Clinical Pharmacy Internal Medicine Pulmonary Diseases |
Journal title:
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Antimicrobial Agents and Chemotherapy
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Abstract:
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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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