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 three Indonesian randomized controlled phase II trials comparing oral rifampicin 450mg (~10mg/kg) to intensified regimens including 750-1350mg orally, or a 600mg intravenous infusion. Pharmacokinetic data from plasma and CSF was 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 two disposition-compartments, saturable clearance and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5% [95%CI 4.4-6.4]) and half-life for distribution plasma to CSF (2.1 h [1.3-2.9]). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 drop-outs) 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 ~50% to ~70% upon increasing the oral rifampicin dose from 10 to 30mg/kg, and that higher doses would further increase 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 30mg/kg to be investigated in phase III clinical trials.

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis

“…EC99) with PTA of 91% (22). Another study investigating Indonesian adults with TBM showed that rifampicin 40 mg/kg/day would be required to reach a PTA around 95% (23). Children studied here required a higher dose of rifampicin compared to adults due to lower plasma rifampicin exposures, resulting from a nonlinear relationship between body weight and drug elimination processes (46).…”

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

“…The PK analysis included 133 individuals and 1150 rifampicin concentrations (170 from CSF) and the survival analysis included 148 individuals of whom 58 died and 15 dropped out. Higher individual plasma rifampicin exposures (AUC 0-24h ), lower age and higher baseline Glasgow coma scale (GCS) scores reduced the hazard of death 38 . Figure 2 shows how 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 38 .…”

“…Higher individual plasma rifampicin exposures (AUC 0-24h ), lower age and higher baseline Glasgow coma scale (GCS) scores reduced the hazard of death 38 . Figure 2 shows how 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 38 . Based on this analysis it was concluded that higher rifampicin exposures early during treatment substantially decrease the risk of death and that optimal dose of rifampicin in treatment of TBM should be further investigated in phase III trials.…”

“…CSF rifampicin concentration is reported to approximately 12% of total (protein-bound plus unbound) plasma concentrations and approximately 50% based on estimated unbound concentrations 24 – 26 . The standard dose of rifampicin is known to often result in CSF concentration below or around the M. tuberculosis minimum inhibitory concentration (MIC) for rifampicin of 0.2–0.4 mg/L 15 .…”

“…However, within the exposure range achieved, no relationship between rifampin exposure and survival was seen within the trial 41 . It is possible, as seen in the PTB model 34 and in TBM PK-PD model 38 , a rifampicin dose of greater than 15mg/kg is required to achieve exposures capable of reducing time to culture conversion and improving survival, which may explain the lack of exposure-response relationship seen in this trial.…”