Semi-physiological pharmacokinetic–pharmacodynamic (PK–PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats. (January 2015)

• Record Type: Journal Article
• Authors: Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji; Sakaeda, Toshiyuki
• Is Part Of: Xenobiotica. Volume 45:Number 1(2015:Jan.)
• Page Start: 19
• Page End: 28
• Publication Date: 2015-01
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.943335
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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.</p> <p>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.</p> <p>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 <italic>AUC</italic>_0–∞ level. The final PK–PD model effectively characterized platelet count data and final PD parameters were estimated with high certainty.</p> <p>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.</p> </abstract>