Population pharmacokinetic analysis of cefditoren pivoxil in pediatric patients with infection.

Abstract

Population pharmacokinetic analysis was conducted on cefditoren pivoxil (CDTR-PI, Brand name: MEIACT, Meiji Seika Pharma Co., Ltd.), a third generation oral antibiotic, using plasma concentrations of cefditoren (CDTR, total number of sampling points: 578) obtained from pediatric patients (153 subjects, dose: 5.62 +/- 1.62 mg/kg) after CDTR-PI administration as well as demographic data of those subjects. NONMEM (Ver. VI LEVEL 2.0) was used as software. The first-order conditional estimation (FOCE) method without interaction was employed as algorithm. A one-compartment model with first-order absorption was used as a pharmacokinetic model. As the result of analysis, the following population pharmacokinetic parameters were obtained for CDTR. Population mean parameters: ka (hr(-1)) = 0.527, CL/F (L/hr/kg) = -0.474 x Scr + 0.82, Vd/F (L/kg) = 0.77, Tlag (hr) = 0.282 x (1+0.435 x NAT) (NAT: 0 = Japan, 1 = USA, interindividual variability: omega (ka) = 17.23%, omega (CL/F) = 33.02%, omega (Vd/F) = 86.66%, intraindividual residual variability: sigma = 0.428 microg/mL. Bayes estimation was carried out for each subject using the final model to calculate secondary parameters such as C(max), T(max), AUC, and t1/2. C(max) and AUC increased significantly with dose. However, T(max) was approximately 2hours and t1/2 was approximately 1 hour at any dose level, showing no significant dose-dependent changes. When CDTR-PI was administered orally to a child, a significant increase was noted in plasma CDTR concentrations, suggesting high efficacy. In addition, pharmacokinetics of CDTR were simulated in patients with renal impairment using the final model. As a result, a delay in T(max) and increases in AUC, C(max), and t1/2 were presumed with increased Scr, and the degrees of such increases were also quantitatively estimated. As mentioned above, the population pharmacokinetic parameters of CDTR were obtained, which is sure contribute to simulation of its plasma concentrations in patients with various backgrounds and to speculation of its efficacy and safety.