title: Pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for erythropenia in rats.
abstract: BACKGROUND
  The aim of the present study was to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model in rats that could predict the onset and degree of erythropenia, a severely toxic side effect that severely limits the use of the anticancer agent 5-fluorouracil (5-FU).
  
  
  METHODS
  Total erythrocyte counts, hemoglobin (Hb) concentrations, and hematocrit (Hct) levels were measured in rats following the intravenous bolus administration of 5-FU for 4 days in order to obtain data for an analysis of the PK-PD model. Our PK-PD model consisted of a two-compartment PK model, with two compartments for the PD model and nine structural PK-PD model parameters.
  
  
  RESULTS
  After the intravenous bolus administration of 5, 10, or 20 mg/kg of 5-FU to rats, absolute erythrocyte counts, Hb concentrations, and Hct levels transiently decreased, reached minimum levels on Days 7-14, and then returned to baseline levels. The nadir values (Cnadir) for rats treated with 5, 10, or 20 mg/kg of 5-FU were significantly decreased to approximately 79.4, 76.3, or 46.5% of the baseline value (Cbaseline) in erythrocyte counts, 86.3, 83.3, or 45.7% of Cbaseline in Hb concentrations, 88.6, 85.5, or 47.1% of Cbaseline in Hct levels, respectively. The PK-PD model effectively captured the features of erythropenia and Cnadir after 5-FU chemotherapy. This PK-PD model was successfully used to characterize the learner relationship between the area under the plasma 5-FU concentration-time curve (AUC0-∞) following the intravenous bolus administration of 5-FU and the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels after the 5-FU treatment.
  
  
  CONCLUSIONS
  The results of the present study suggest that the administration of a pharmacokinetically modified dose of 5-FU could minimize the Cnadir in erythrocyte counts, Hb concentrations, and Hct levels following the administration of 5-FU. The PK-PD model and simulation represent valuable approaches for quantifying and predicting erythropenia as well as determining individual doses and the time at which the subsequent course of the treatment should start.
authors: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors: Shinji
authors: S
authors: Kobuchi
authors: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. Electronic address: yukako@mb.kyoto-phu.ac.jp.
authors: Yukako
authors: Y
authors: Ito
authors: Department of Pharmacy, Otsu Municipal Hospital, Otsu, Shiga 520-0804, Japan.
authors: Taro
authors: T
authors: Hayakawa
authors: Department of Biopharmaceutics, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
authors: Asako
authors: A
authors: Nishimura
authors: Department of Biopharmaceutics, Doshisha Women's College of Liberal Arts, Kyotanabe, Kyoto 610-0395, Japan.
authors: Nobuhito
authors: N
authors: Shibata
authors: BioSerenTach. Inc., Shimogyo-ku, Kyoto 600-8040, Japan.
authors: Kanji
authors: K
authors: Takada
authors: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors: Toshiyuki
authors: T
authors: Sakaeda
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000187:drug effects*; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D006454:Hemoglobins; D005472:Fluorouracil
keywords: 5-Fluorouracil; Anticancer drug; Erythropenia; Hematocrit; Hemoglobin; Methods; Myelosuppression; Pharmacokinetic–pharmacodynamic model; Rat