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Antimicrob Agents Chemother. 2018 Nov 26;62(12). pii: e01014-18. doi: 10.1128/AAC.01014-18. Print 2018 Dec.

Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis.

Author information

1
Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands sofiatidian@gmail.com.
2
Department of Neurology, Faculty of Medicine, Universitas Padjadjaran Hasan Sadikin Hospital, Bandung, Indonesia.
3
TB/HIV Research Centre, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
4
Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
5
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
6
Division of Epidemiology and Biostatistics, Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
7
Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
8
Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

Abstract

High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0-24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.).

KEYWORDS:

Indonesia; Mycobacterium tuberculosis ; RCT; meningeal; pharmacokinetics; rifampin; survival; tolerability

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