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Xenobiotica
the fate of foreign compounds in biological systems
Volume 45, 2015 - Issue 1
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Research Article

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

, , , , , & show all
Pages 19-28 | Received 06 Jun 2014, Accepted 07 Jul 2014, Published online: 22 Jul 2014
 

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.

Declaration of interest

This study was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 24590223) from MEXT (Ministry of Education, Culture, Sports, Science and Technology) of Japan.

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