Background: Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited paediatric pharmacokinetic data to inform dose selection for children.
Methods: Children routinely receiving levofloxacin (250 mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following a 15 or 20 mg/kg dose, given as whole tablet(s) or crushed, orally, or by nasogastric tube. Pharmacokinetic parameters were estimated using non-linear mixed effects modelling. Model-based simulations were performed to estimate doses across weight bands that would achieve adult exposures with 750mg once-daily dosing.
Results: 109 children were included, median age 2.1 years (range 0.3–8.7); median weight 12 kg (range 6–22). Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterised age-driven maturation of clearance (CL) with an effect reaching 50% around 2 months after birth and 100% by 2 years of age.. CL in a typical child (12 kg, 2-year-old) was 4.7 L/h. HIV infection reduced CL by 16%. Using the adult 250 mg formulation, Levofloxacin exposures were substantially lower than those reported in adults receiving a similar mg/kg dose. To achieve adult-equivalent exposures at a 750 mg daily dose, higher levofloxacin paediatric doses may be required -from 18 mg/kg/day for younger children with weights 3-4 kg (due to immature clearance) to 40 mg/kg/day for older children.
Conclusions: Currently recommended doses of levofloxacin for MDR-TB in children result in exposures considerably lower than in adults. The effect of different formulations and formulation manipulation require further investigation.
We recommend age- and weight-banded doses of 250 mg tablets adult-formulation most likely to achieve target concentrations for prospective evaluation.
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