Pharmacokinetics and safety of ofloxacin in children with drug-resistant tuberculosis

Anthony J. Garcia-Prats, Heather R. Draper, Stephanie Thee, Kelly E. Dooley, Helen M. McIlleron, James A. Seddon, Lubbe Wiesner, Sandra Castel, H. Simon Schaaf, Anneke C. Hesseling

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6073-6079
Number of pages7
JournalAntimicrobial agents and chemotherapy
Volume59
Issue number10
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Garcia-Prats, A. J., Draper, H. R., Thee, S., Dooley, K. E., McIlleron, H. M., Seddon, J. A., Wiesner, L., Castel, S., Schaaf, H. S., & Hesseling, A. C. (2015). Pharmacokinetics and safety of ofloxacin in children with drug-resistant tuberculosis. Antimicrobial agents and chemotherapy, 59(10), 6073-6079. https://doi.org/10.1128/AAC.01404-15