Pediatric tuberculous meningitis: model-based approach to determining optimal doses of anti-tuberculosis drugs for children

Post Date: 
2015-10-22
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Clinical Sites: 
Publication: 
Clinical Pharmacology and Therapeutics
Summary: 


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.

Citation: 
Savic R, Ruslami R, Hibma J, Hessling A, Ramachandran G, Gamiem AR, Swaminathan S, Mcilleron H, Gupta A, Thakur K, vanCrevel R, Aarnoutse R, Dooley K. Pediatric tuberculous meningitis: model-based approach to determining optimal doses of anti-tuberculosis drugs for children. Clin Pharmacol Ther. 2015 Oct 22. doi:10.1002/cpt.202.
Collaborators: 


  • Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA

  • Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia

  • Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa

  • National Institute for Research in Tuberculosis, Chetpet, Chennai, India

  • Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

  • Radboud University Medical Center, Nijmegen, The Netherlands