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

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.

Conflict of interest statement

CONFLICT OF INTEREST/DISCLOSURE

The authors report no Conflicts of Interest.

© 2015 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Population PK model to describe plasma and CSF data from adults taking rifampicin as part of multidrug treatment for tuberculous meningitis.

Figure 2

Exposure-response relationship between rifampin plasma AUC0–24 and survival in tuberculosis meningitis patients. The continuous line represents the median for the simulated data and shaded region represents the 90% confidence interval for the median of the simulated data. The AUC that predicts 99% of maximal response is 92 mg*h/L, which is indicated in the figure by the x-intercept line.

Figure 3

Range of rifampin doses in a simulated population of children with TB meningitis needed to achieve the target area under the concentration-time curve (AUC) of 92 mg*h/L, by weight and age. Black bars represent the range for intravenous dosing and grey bars represent the range for oral dosing.