Unknown

Dataset Information

0

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


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.).

SUBMITTER: Dian S 

PROVIDER: S-EPMC6256787 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Dian S S   Yunivita V V   Ganiem A R AR   Pramaesya T T   Chaidir L L   Wahyudi K K   Achmad T H TH   Colbers A A   Te Brake L L   van Crevel R R   Ruslami R R   Aarnoutse R R  

Antimicrobial agents and chemotherapy 20181126 12


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 com  ...[more]

Similar Datasets

| S-EPMC5947135 | biostudies-literature
| S-EPMC5862527 | biostudies-literature
| S-EPMC8920328 | biostudies-literature
| S-EPMC8916538 | biostudies-literature
| S-EPMC8064362 | biostudies-literature
| S-EPMC4608181 | biostudies-literature
| S-EPMC6360528 | biostudies-literature
| S-EPMC7542255 | biostudies-literature
| S-EPMC3722440 | biostudies-literature