Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis.

Abstract

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

• Authors: Paolo Denti, Anthony J Garcia-Prats, Heather R Draper, Lubbe Wiesner, Jana Winckler, Stephanie Thee, Kelly E Dooley, Rada M Savic, Helen M McIlleron, H Simon Schaaf, Anneke C Hesseling
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 62 Issue 2 (02 2018) ISSN: 1098-6596 [Electronic] United States
• PMID: 29133560 (Publication Type: Journal Article, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 American Society for Microbiology.

Chemical References

• Anti-HIV Agents
• Antitubercular Agents
• Tablets
• Levofloxacin

Topics

• Anti-HIV Agents (therapeutic use)
• Antiretroviral Therapy, Highly Active
• Antitubercular Agents (blood, pharmacokinetics, pharmacology)
• Area Under Curve
• Child
• Child, Preschool
• Coinfection
• Drug Administration Schedule
• Drug Dosage Calculations
• Female
• HIV (drug effects, growth & development)
• HIV Infections (blood, drug therapy, virology)
• Humans
• Infant
• Levofloxacin (blood, pharmacokinetics, pharmacology)
• Male
• Models, Statistical
• Mycobacterium tuberculosis (drug effects, growth & development)
• Prospective Studies
• South Africa
• Tablets
• Tuberculosis, Multidrug-Resistant (blood, drug therapy, microbiology)