title: 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.
abstract: 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. 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. 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 (AUC0-∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r2=0.989, 0.877 and 0.956, respectively. 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.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto , Japan .
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Taro
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Shota
authors.initials: S
authors.lastname: Kuwano
authors.forename: Akiko
authors.initials: A
authors.lastname: Baba
authors.forename: Kota
authors.initials: K
authors.lastname: Shinohara
authors.forename: Asako
authors.initials: A
authors.lastname: Nishimura
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D003198:Computer Simulation; D005472:Fluorouracil / Q000493:pharmacokinetics*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D005472:Fluorouracil
keywords: Cancer chemotherapy; PK–PD modeling; myelosuppression; simulations; toxicity