Abstract
BackgroundIntensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.MethodsAn individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750–1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.ResultsPharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%–6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3–2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival.ConclusionsHigher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.
Highlights
Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown
The antimicrobial treatment of Tuberculous meningitis (TBM) is traditionally based on the guidelines for pulmonary TB, a combination therapy with rifampicin as the pivotal component [7]
The crucial role of rifampicin is underlined by the excessively high mortality rates in patients with TBM with resistance to rifampicin [8, 9]; this, even though it is known that penetration of rifampicin into cerebrospinal fluid (CSF) is very limited [10]
Summary
Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis. Our objective was to characterize the population pharmacokinetics of high-dose rifampicin
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