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: 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
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 10 Pg. 6073-9 (Oct 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26195507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antitubercular Agents
• Ofloxacin

Topics

• Adolescent
• Antitubercular Agents (adverse effects, pharmacokinetics, therapeutic use)
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Ofloxacin (adverse effects, pharmacokinetics, therapeutic use)
• Prospective Studies
• Tuberculosis, Multidrug-Resistant (blood, drug therapy)