DDMODEL00000134: Tsukamoto 2001 PBPK/PD Model for Capecitabine

  public model
Short description:
A PBPK model was developed by Tsukamoto et al., 2001 to describe and better understand the physiological processes behind the clinical disposition of capecitabine and its three metabolites. The metabolism of capecitabine is sequential, and ultimately leads to the production of the active metabolite, 5-FU. The PBPK model was used to further understand the tissue selectivity of 5-FU using in vitro metabolism data. It was shown that non-linear elimination of 5-FU in tumour tissue leads to accumulation of 5-FU in the site of action.
Original code
  • A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans: the mechanism for tumor-selective accumulation of 5-FU.
  • Tsukamoto Y, Kato Y, Ura M, Horii I, Ishitsuka H, Kusuhara H, Sugiyama Y
  • Pharmaceutical research, 8/2001, Volume 18, Issue 8, pages: 1190-1202
  • Department of Preclinical Science, Nippon Roche Research Center, Kamakura, Kanagawa, Japan.
  • PURPOSE: To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans. METHOD: The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations. RESULTS: The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges. CONCLUSIONS: It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.
Sonya Tate
Context of model development: Mechanistic Understanding;
Discrepancy between implemented model and original publication: From visual comparison to the reported graphs, it can be seen that the concentration-time profiles of each tissue and compound are largely reproduced, with the exception of the 5-FU simulations (Figure 4(D)). The model has been checked for consistency by S. Tate and I. Gueorguieva, and no errors in the model encoding were found. ;
Long technical model description: A PBPK model was developed by Tsukamoto et al., 2001 to describe and better understand the physiological processes behind the clinical disposition of capecitabine and its three metabolites. The metabolism of capecitabine is sequential, and ultimately leads to the production of the active metabolite, 5-FU. The PBPK model was used to further understand the tissue selectivity of 5-FU using in vitro metabolism data. It was shown that non-linear elimination of 5-FU in tumour tissue leads to accumulation of 5-FU in the site of action.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: Yes;
Modelling context description: PBPK/PD modelling of capecitabine;
Modelling task in scope: simulation;
Nature of research: Preclinical development;
Therapeutic/disease area: Oncology;
Annotations are correct.
This model is not certified.
  • Model owner: Sonya Tate
  • Submitted: Oct 16, 2016 5:04:12 PM
  • Last Modified: Oct 16, 2016 5:04:12 PM
Revisions
  • Version: 10 public model Download this version
    • Submitted on: Oct 16, 2016 5:04:12 PM
    • Submitted by: Sonya Tate
    • With comment: Edited model metadata online.
 
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