Population pharmacokinetics and pharmacodynamics of tosufloxacin granules in pediatric infectious diseases

The population pharmacokinetics and pharmacodynamics(PK-PD) of 10% tosufloxacin granules(TFLX) were performed in pediatric infectious diseases in Japanese. Infants and children aged (1-15 years old) with bacterial pneumonia or acute otitis media were orally administered a dose of either 4 mg/kg TFLX (not exceeding 120 mg per dose) or 6 mg/kg TFLX (not exceeding 180 mg per dose) twice daily, and 416 plasma concentrations were measured from 222 pediatric subjects were obtained. Population pharmacokinetic parameters were estimated using a nonlinear mixed effect model(NONMEM), applying a one-compartment model with first-order absorption as a pharmacokinetic model. Covariates were tested for their potential influence on TFLX pharmacokinetics. Significant influence of body weight was found in oral clearance(CL/F) and volume of distribution(Vd/F). Plasma TFLX concentrations versus a time profile of 4 mg/kg TFLX in pediatric subjects were similar to those between 200 mg TFLX and 100 mg TFLX in adults. Pharmacokinetic parameters of 4 mg/kg TFLX in pediatric subjects were similar to those of 200 mg TFLX in adults. The attaining probability of target unbound fractions of AUC/MIC(fAUC/MIC) in those administered 4 or 6 mg/kg TFLX was calculated by Monte Carlo simulation. A twice-daily oral dose of 4 mg/kg TFLX is expected to show superior clinical efficacy against Streptococcus pneumoniae, Moraxella(Branhamella) catarrhalis, and Haemophilus influenzae. These results indicate that 4.1 mg/kg TFLX (OZEX® 15% granules, 6 mg/kg tosufloxacin tosilate hydrate) twice daily is effective.