Dataset Information

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.

SUBMITTER: Svensson EM

PROVIDER: S-EPMC7643733 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Svensson Elin M EM Dian Sofiati S Te Brake Lindsey L Ganiem Ahmad Rizal AR Yunivita Vycke V van Laarhoven Arjan A Van Crevel Reinout R Ruslami Rovina R Aarnoutse Rob E RE

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20201101 8

<h4>Background</h4>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.<h4>Methods</h4>An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampici ...[more]

PMID: 31665299

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Project description:BackgroundThe differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a diagnostic model that could accurately distinguish TBM from BM.MethodsPatients with TBM or BM were recruited between January 2017 and January 2021 at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The detection for indicators involved in cerebrospinal fluid (CSF) and T-SPOT assay were performed simultaneously. Multivariate logistic regression was used to create a diagnostic model.ResultsA total of 174 patients (76 TBM and 98 BM) and another 105 cases (39 TBM and 66 BM) were enrolled from Qiaokou cohort and Caidian cohort, respectively. Significantly higher level of CSF lymphocyte proportion while significantly lower levels of CSF chlorine, nucleated cell count, and neutrophil proportion were observed in TBM group when comparing with those in BM group. However, receiver operating characteristic (ROC) curve analysis showed that the areas under the ROC curve (AUCs) produced by these indicators were all under 0.8. Meanwhile, tuberculosis-specific antigen/phytohemagglutinin (TBAg/PHA) ratio yielded an AUC of 0.889 (95% CI, 0.840-0.938) in distinguishing TBM from BM, with a sensitivity of 68.42% (95% CI, 57.30%-77.77%) and a specificity of 92.86% (95% CI, 85.98%-96.50%) when a cutoff value of 0.163 was used. Consequently, we successfully established a diagnostic model based on the combination of TBAg/PHA ratio, CSF chlorine, CSF nucleated cell count, and CSF lymphocyte proportion for discrimination between TBM and BM. The established model showed good performance in differentiating TBM from BM (AUC: 0.949; 95% CI, 0.921-0.978), with 81.58% (95% CI, 71.42%-88.70%) sensitivity and 91.84% (95% CI, 84.71%-95.81%) specificity. The performance of the diagnostic model obtained in Qiaokou cohort was further validated in Caidian cohort. The diagnostic model in Caidian cohort produced an AUC of 0.923 (95% CI, 0.867-0.980) with 79.49% (95% CI, 64.47%-89.22%) sensitivity and 90.91% (95% CI, 81.55%-95.77%) specificity.ConclusionsThe diagnostic model established based on the combination of four indicators had excellent utility in the discrimination between TBM and BM.

Project description:Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral dosing of 35 mg/kg of body weight and intravenous dosing of 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. We performed a randomized parallel-group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using noncompartmental analysis, and exposures were compared by geometric mean ratios (GMRs). Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high-dose oral, n = 15; intravenous, n = 14). The median CD4 count was 130 cells/mm3 (interquartile range [IQR], 66 to 253 cells/mm3). The rifampicin geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) values were 42.9 μg · h/ml (95% confidence interval [CI], 24.5 to 75.0 μg · h/ml) for the standard dose, 295.2 μg · h/ml (95% CI, 189.9 to 458.8 μg · h/ml) for the high oral dose, and 206.5 μg · h/ml (95% CI, 154.6 to 275.8 μg · h/ml) for intravenous administration. The rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 to 2.21) and the maximal concentration of drug in serum (Cmax) GMR was 0.89 (90% CI, 0.63 to 1.23) for high-dose oral administration with respect to intravenous dosing. The plasma rifampicin AUC0-24 was higher after an oral 35-mg/kg dose than with intravenous administration at a 20-mg/kg dose over the first few days of tuberculosis (TB) treatment. The findings support oral rifampicin dosing in future tuberculous meningitis trials.

Dataset Information

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

Publications

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

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