Semi-physiological pharmacokinetic–pharmacodynamic modeling and simulation of 5-fluorouracil for the whole time course of alterations in leukocyte, neutrophil and lymphocyte counts in rats. (September 2014)

• Record Type: Journal Article
• Authors: Kobuchi, Shinji; Ito, Yukako; Hayakawa, Taro; Kuwano, Shota; Baba, Akiko; Shinohara, Kota; Nishimura, Asako; Shibata, Nobuhito; Takada, Kanji
• Is Part Of: Xenobiotica. Volume 44:Number 9(2014:Sep.)
• Page Start: 804
• Page End: 818
• Publication Date: 2014-09
• 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: 10.3109/00498254.2014.900588
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. We aimed to develop a simple pharmacokinetic–pharmacodynamic (PK–PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats.</p> <p>2. Our PK–PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model.</p> <p>3. The semi-physiological PK–PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK–PD analytical simulation curves against the area under the plasma 5-FU concentration–time curve (<italic>AUC</italic>_0–∞) after intravenous administration of 5-FU, a linear relationship was inferred, with <italic>r</italic>²= 0.989, 0.877 and 0.956, respectively.</p> <p>4. The semi-physiological PK–PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.</p> </abstract>