Vol.58 No.S-2 October 2010
Population pharmacokinetics and pharmacodynamics of tosufloxacin granules in pediatric infectious diseases
1)Department of Research Project Studies, Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan
2)Formerly: Department of Pediatrics, Meitetsu Hospital
3)Infection Control Center, Keio University School of Medicine
4)Department of Pediatrics, Kawasaki Medical School
5)Department of Pediatrics, Asahikawa-Kosei General Hospital
6)Department of Otolaryngology, Second Hospital, Fujita Health University, School of Medicine
7)Department of Otolaryngology, Saitama Medical Center Jichi Medical University
8)Department of Otolaryngology, National Center for Child Health and Development
9)Department of Nutrition, Faculty of Health Care Science, Chiba Prefecture University of Health Sciences
10)Biostatistics Group, Development Division, Toyama Chemical. Co.,Ltd.
Abstract
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.
Key word
tosufloxacin, population pharmacokinetics, PK-PD, child, dose finding
Received
May 10, 2010
Accepted
September 2, 2010
Jpn. J. Chemother. 58 (S-2): 69-77, 2010
