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

• Published in: Clinical infectious diseases 2024-03, Vol.78 (3), p.756-764
• Main Authors: White, Yasmine N, Solans, Belen P, Denti, Paolo, van der Laan, Louvina E, Schaaf, H Simon, Vonasek, Bryan, Malik, Amyn A, Draper, Heather R, Hussain, Hamidah, Hesseling, Anneke C, Garcia-Prats, Anthony J, Savic, Radojka M
• Format: Article
• Language: English
• Subjects: Major
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciae024

Abstract Background 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. Methods 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. Results 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