title: Population Pharmacokinetic-Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats.
abstract: OBJECTIVE
  Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic-pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats.
  
  
  METHODS
  Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic-pharmacodynamic model.
  
  
  RESULTS
  The population pharmacokinetic model consisting of a two-compartment model with Michaelis-Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic-pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity.
  
  
  CONCLUSIONS
  This population pharmacokinetic-pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan. kobuchi@mb.kyoto-phu.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood* / Q000633:toxicity*; D001772:Blood Cell Count; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000097:blood* / Q000633:toxicity*; D006801:Humans; D008297:Male; D008954:Models, Biological; D017208:Rats, Wistar; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil