title: Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis.
abstract: Ofloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC0-24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (Cmax), AUC0-8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC0-24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC0-24 was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47; P = 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa garciaprats@sun.ac.za.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Garcia-Prats
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Draper
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa Department of Paediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Thee
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McIlleron
authors.affiliation: Department of Paediatrics, Imperial College London, London, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Seddon
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Sandra
authors.initials: S
authors.lastname: Castel
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: H Simon
authors.initials: HS
authors.lastname: Schaaf
authors.affiliation: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Anneke C
authors.initials: AC
authors.lastname: Hesseling
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015242:Ofloxacin / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D015242:Ofloxacin