DOI: 10.1093/cid/ciae024 ISSN: 1058-4838

Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis

Yasmine N White, Belen P Solans, Paolo Denti, Louvina E van der Laan, H Simon Schaaf, Bryan Vonasek, Amyn A Malik, Heather R Draper, Hamidah Hussain, Anneke C Hesseling, Anthony J Garcia-Prats, Radojka M Savic
  • Infectious Diseases
  • Microbiology (medical)



Each year 25 000–32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.


Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)–recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.


Data from 242 children (2.8 years [0.2–16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16–33 mg/kg for dispersible tablets or 16–50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax.


Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

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