Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials

Abstract

Background: Intensified 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.

Methods: An 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.

Results: Pharmacokinetic 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.

Conclusions: Higher 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.

Keywords: exposure response; optimal dosing; pharmacometrics; rifampicin; tuberculous meningitis.

Figure 1.

Visualization of the impact of predictors on the hazard governing survival. Depicted ranges of age, Glasgow Coma Scale (GCS) score, and plasma rifampicin area under the rifampicin plasma concentration curve from 0 to 24 hours after dose (AUC_0-24h) at day 2 ± 1 correspond to the observed values in the population included in this analysis. The gray shaded areas represent 90% confidence intervals based on bootstrap results.

Figure 2.

Model-predicted proportion survival over time representative for typical patients (age 30 years, baseline Glasgow Coma Scale score = 13) per plasma rifampicin exposure level (area under the rifampicin plasma concentration curve from 0 to 24 hours after dose at day 2 ± 1). Abbreviations: IV, intravenously; PO, orally.