title: Semi-physiological pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats.
abstract: 1. The aim of this study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model that could characterize the complete time-course of alterations in platelet counts to predict the onset and degree of thrombocytopenia, which severely limits the use of the anticancer agent 5-fluorouracil (5-FU), in rats. 2. Platelet counts were measured in rats following the intravenous administration of various doses of 5-FU for 4 days to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with three compartments for the PD model and 10 structural PK-PD model parameters. 3. After the 5-FU treatment, platelet counts transiently decreased to a nadir level, showed a rebound to above the baseline level before recovering to baseline levels. Nadir platelet counts and rebounds varied with the AUC0-∞ level. The final PK-PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty. 4. This PK-PD model and simulation may represent a valuable tool for quantifying and predicting the complete time-course of alterations in blood cell counts, and could contribute to the development of therapeutic strategies with 5-FU and assessments of various novel anticancer agents that are difficult to examine in humans.
authors: Department of Pharmacokinetics, Kyoto Pharmaceutical University , Kyoto , Japan .
authors: Shinji
authors: S
authors: Kobuchi
authors: Yukako
authors: Y
authors: Ito
authors: Taro
authors: T
authors: Hayakawa
authors: Asako
authors: A
authors: Nishimura
authors: Nobuhito
authors: N
authors: Shibata
authors: Kanji
authors: K
authors: Takada
authors: Toshiyuki
authors: T
authors: Sakaeda
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D003198:Computer Simulation; D005472:Fluorouracil / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D010976:Platelet Count; D011897:Random Allocation; D017208:Rats, Wistar; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil
keywords: Cancer chemotherapy; PK–PD modeling; myelosuppression; platelet; simulations; toxicity