Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children.  

Clinical Pharmacology and Therapy; 2015; 98; 622-629.         

Abstract: Pediatric tuberculous meningitis (TBM) is a highly morbid, often fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic (PK) and outcomes data from adult TBM trials plus plasma PK data from children. A population PK/pharmacodynamic (PD) model using adult data defined rifampin target exposures (plasma area under the curve (AUC) 0–24 = 92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously (i.v.). From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19–33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results.

Study Highlights :

What is the current knowledge on the topic?

Pediatric TBM has high morbidity and mortality. Optimal treatment is not established for children, but recent clinical trials in adults suggest higher doses of rifamycins and use of fluoroquinolones may improve outcomes.

What question does this study address?

In this study, we used plasma and cerebrospinal PK data and outcomes data from a successful adult TBM clinical trial to establish target exposures associated with reduced mortality and to describe CSF penetration of rifampin in adults with TBM. We then gathered rifampin and levofloxacin plasma PK data from children with TB to determine pediatric doses required to achieve target concentrations.

What this study adds to our knowledge?

The target plasma AUC0–24 for rifampin for treating adult TBM is 92 mg*h/L. The fraction of rifampin in CSF, or CSF:plasma ratio, was 0.082. To reach adult exposure targets, we estimate that children need daily rifampin doses of at least 15 mg/kg i.v. or 30 mg/kg orally. Levofloxacin doses required to achieve targets are provided.

How this might change clinical pharmacology and therapeutics?

Rifampin given at currently recommended doses for pediatric TBM fails to achieve target concentrations, and CSF exposures are unlikely to surpass the mean inhibitory concentration of rifampin against M. tuberculosis . Higher doses of rifampin and/or use of levofloxacin may improve survival. Our study provides dosing recommendations for upcoming trials aimed at optimizing pediatric TBM treatment, in which the PK, safety, and efficacy of these doses can be confirmed.

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