title: 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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors.forename: R
authors.initials: R
authors.lastname: Ruslami
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Hibma
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa.
authors.forename: A
authors.initials: A
authors.lastname: Hesseling
authors.affiliation: National Institute for Research in Tuberculosis, Chetpet, Chennai, India.
authors.forename: G
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors.forename: A R
authors.initials: AR
authors.lastname: Ganiem
authors.affiliation: National Institute for Research in Tuberculosis, Chetpet, Chennai, India.
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: H
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Thakur
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Aarnoutse
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Dooley
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D054796:Drug Dosage Calculations; D006801:Humans; D007223:Infant; D064704:Levofloxacin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016032:Randomized Controlled Trials as Topic; D012293:Rifampin / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D014390:Tuberculosis, Meningeal / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D064704:Levofloxacin; D012293:Rifampin