Oxford University Press, Journal of Antimicrobial Chemotherapy, 10(78), p. 2481-2488, 2023
DOI: 10.1093/jac/dkad257
Full text: Unavailable
Abstract Background Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding. Methods We conducted a crossover pharmacokinetic trial in children aged ≤5 years receiving levofloxacin RR-TB preventive therapy. Pharmacokinetic sampling was done after 15–20 mg/kg doses of levofloxacin with 100 mg dispersible and crushed 250 mg non-dispersible levofloxacin formulations. A population pharmacokinetic model was developed. Results Twenty-five children were included, median (IQR) weight and age 12.2 (10.7–15.0) kg and 2.56 (1.58–4.03) years, respectively. A two-compartment model with first-order elimination and transit compartment absorption best described levofloxacin pharmacokinetics. Allometric scaling adjusted for body size, and maturation of clearance with age was characterized. Typical clearance in a 12 kg child was estimated at 4.17 L/h. Non-dispersible tablets had 21.5% reduced bioavailability compared with the dispersible formulation, with no significant differences in other absorption parameters. Dosing simulations showed that current recommended dosing for both formulations result in median exposures below adult-equivalent exposures at a 750 mg daily dose, mainly in children >6 months. Higher levofloxacin doses of 16–30 mg/kg for dispersible and 20–38 mg/kg for crushed non-dispersible tablets may be required in children >6 months. Conclusions The dispersible paediatric levofloxacin formulation has improved bioavailability compared with the crushed non-dispersible adult formulation, but exposures remain below those in adults. We propose optimized age- and weight-based dosing for levofloxacin, which require further evaluation.