Steady-State Pharmacokinetics of Phenytoin from Routinely Collected Patient Data

Authors: Grasela TH, Sheiner LB, Rambeck B, Boenigk HE, Dunlop A, Mullen PW, Wadsworth J, Richens A, Ishizaki T, Chiba K, Miura H, Minagawa K, Blain PG, Mucklow JC, Bacon CT, Rawlins M
Publication: Clin Pharmacokinet
Keywords: adolescent, adult, AED, analysis, biological, central nervous system agents, female, humans, kinetics, male, metabolism, models, NONMEM, pharmacokinetics, phenytoin, population, research support, U.S. Government
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Previously reported routine Phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 ± 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information.

Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients.

Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20%, and approximately 50% respectively.

By Thaddeus H. Grasela, L. B. Sheiner, B. Rambeck, H. E. Boenigk, A. Dunlop, P. W. Mullen, J. Wadsworth, A. Richens, T. Ishizaki, K. Chiba, H. Miura, K. Minagawa, P. G. Blain, J. C. Mucklow, C. T. Bacon, & M. Rawlins