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A Physiologically Based Pharmacokinetic–Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Capecitabine is an oral prodrug of 5-fluorouracil and is widely used for colorectal cancer (CRC) treatment. However, knowledge of its antitumor efficacy after modification of the dosing schedule is insufficient. The aim of this study was to predict the antitumor efficacy of capecitabine using a physiologically based pharmacokinetic–pharmacodynamic (PBPK-PD) model based on metabolic enzyme activities.

Methods

CRC model rats were administrated 180 mg/kg of capecitabine for 2 weeks. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 h following capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured on days 1, 7, and 14. Metabolic enzyme activities were determined in vitro using the liver and small intestine of the CRC model rats. A PBPK-PD model was developed based on metabolic enzyme activities. The antitumor efficacy of capecitabine after regimen modification was simulated using the PBPK-PD model.

Results

Capecitabine antitumor efficacy was dose-dependent. A dose of > 500 μmol/kg was needed to inhibit tumor growth. After capecitabine regimen modification, a 1-week postponement of capecitabine administration was more efficacious than a reduction in the dosage to 80%.

Conclusions

The PBPK-PD model could simulate the antitumor efficacy at various capecitabine administration schedules. PBPK-PD models can contribute to the development of an appropriate CRC chemotherapy regimen with capecitabine.

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Authors and Affiliations

  1. Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan

    Shuhei Sakai, Shinji Kobuchi, Yukako Ito & Toshiyuki Sakaeda

Authors
  1. Shuhei Sakai
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  2. Shinji Kobuchi
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  3. Yukako Ito
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  4. Toshiyuki Sakaeda
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Corresponding author

Correspondence to Toshiyuki Sakaeda.

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Funding

This work did not receive special funding.

Conflict of interest

SS, SK, YI, and TS have no conflict of interests to declare.

Ethics approval

All experimental procedures using animals were approved by an institutional review board and performed per the Kyoto Pharmaceutical University Guidelines for Animal Experimentation.

Code availability

Non-compartment analysis and modeling were performed with Phoenix WinNonlin® software (version 6.4, Certara USA, Inc., Princeton, NJ, USA)

Author contributions

TS conceptualization; SS, SK, and YI methodology; SS, SK, and YI formal analysis and investigation; SS writing original draft; SK, YI, and TS review and editing the original draft; and TS supervision.

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Sakai, S., Kobuchi, S., Ito, Y. et al. A Physiologically Based Pharmacokinetic–Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules. Eur J Drug Metab Pharmacokinet 46, 301–315 (2021). https://doi.org/10.1007/s13318-021-00674-4

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  • DOI: https://doi.org/10.1007/s13318-021-00674-4

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