Skip to main content
SpringerLink
Log in

Population Pharmacokinetic–Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Myelosuppression is a dose-limiting toxicity of 5-fluorouracil (5-FU). Predicting the inter- and intra-patient variability in pharmacokinetics and toxicities of 5-FU may contribute to the individualized medicine. This study aimed to establish a population pharmacokinetic–pharmacodynamic model that could evaluate the inter- and intra-individual variability in the plasma 5-FU concentration, 5-FU-induced body weight loss and myelosuppression in rats.

Method

Plasma 5-FU concentrations, body weight loss, and blood cell counts in rats following the intravenous administration of various doses of 5-FU for 4 days were used to develop the population pharmacokinetic–pharmacodynamic model.

Results

The population pharmacokinetic model consisting of a two-compartment model with Michaelis–Menten elimination kinetics successfully characterized the individual and population predictions of the plasma concentration of 5-FU and provided credible parameter estimates. The estimates of inter-individual variability in maximal rate of saturable metabolism and residual variability were 8.1 and 22.0%, respectively. The population pharmacokinetic–pharmacodynamic model adequately described the individual complete time-course of alterations in body weight loss, erythrocyte, leukocyte, and lymphocyte counts in rats treated with various doses of 5-FU. The inter-individual variability of the drug effects in the pharmacodynamic model for body weight loss was 82.6%, which was relatively high. The results of the present study suggest that not only individual fluctuations in the 5-FU concentration but also the cell sensitivity would affect the onset and degree of 5-FU-induced toxicity.

Conclusion

This population pharmacokinetic–pharmacodynamic model could evaluate the inter- and intra-individual variability in drug-induced toxicity and guide the assessments of novel anticancer agents in drug development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kochi M, Akiyama Y, Aoki T, et al. FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study. Cancer Chemother Pharmacol. 2013;72:1097–102.

    Article  CAS  PubMed  Google Scholar 

  2. Saif MW, Choma A, Salamone SJ, et al. Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J Natl Cancer Inst. 2009;101:1543–52.

    Article  CAS  PubMed  Google Scholar 

  3. Sakaeda T, Yamamori M, Kuwahara A, et al. Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy. Adv Drug Deliv Rev. 2009;61:388–401.

    Article  CAS  PubMed  Google Scholar 

  4. Ishikura S, Nihei K, Ohtsu A, et al. Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic esophagus. J Clin Oncol. 2003;21:2697–702.

    Article  CAS  PubMed  Google Scholar 

  5. Kumekawa Y, Kaneko K, Ito H, et al. Late toxicity in complete response cases after definitive chemoradiotherapy for esophageal squamous cell carcinoma. J Gastroenterol. 2006;41:425–32.

    Article  CAS  PubMed  Google Scholar 

  6. Tahara M, Ohtsu A, Hironaka S, et al. Clinical impact of criteria for complete response (CR) of primary site to treatment of esophageal cancer. Jpn J Clin Oncol. 2005;35:316–23.

    Article  PubMed  Google Scholar 

  7. Tamura T, Kuwahara A, Kadoyama K, et al. Effects of bolus injection of 5-fluorouracil on steady-state plasma concentrations of 5-fluorouracil in Japanese patients with advanced colorectal cancer. Int J Med Sci. 2011;8:406–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Capitain O, Asevoaia A, Boisdron-Celle M, et al. Individual fluorouracil dose adjustment in FOLFOX base on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study. Clin Colorectal Cancer. 2012;11:263–7.

    Article  CAS  PubMed  Google Scholar 

  9. Gamelin E, Delva R, Jacob J, et al. Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2099–105.

    Article  CAS  PubMed  Google Scholar 

  10. Stec R, Bodnar L, Smoter M, et al. Mitomycin C and high-dose 5-fluorouracil with folinic acid as a therapeutic option for heavily pretreated patients with metastatic colorectal cancer: prospective phase II trial. Oncologist. 2014;19:356–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kobuchi S, Ito Y, Hayakawa T, et al. 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. Xenobiotica. 2014;44:804–18.

    Article  CAS  PubMed  Google Scholar 

  12. Kobuchi S, Ito Y, Hayakawa T, et al. Pharmacokinetic–pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for erythropenia in rats. J Pharmacol Toxicol Methods. 2014;70:134–44.

    Article  CAS  PubMed  Google Scholar 

  13. Kobuchi S, Ito Y, Hayakawa T, et al. Semi-physiological pharmacokinetic–pharmacodynamic (PK-PD) modeling and simulation of 5-fluorouracil for thrombocytopenia in rats. Xenobiotica. 2015;45:19–28.

    Article  CAS  PubMed  Google Scholar 

  14. Friberg LE, Freijs A, Sandström M, et al. Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats. J Pharmacol Exp Ther. 2000;295:734–40.

    CAS  PubMed  Google Scholar 

  15. Kobuchi S, Ito Y, Okada K, et al. Pre-therapeutic assessment of plasma dihydrouracil/uracil ratio for predicting the pharmacokinetic parameters of 5-fluorouracil and tumor growth in a rat model of colorectal cancer. Biol Pharm Bull. 2013;36:907–16.

    Article  CAS  PubMed  Google Scholar 

  16. Kobuchi S, Ito Y, Okada K, et al. Pharmacokinetic/pharmacodynamic modeling of 5-fluorouracil by using a biomarker to predict tumor growth in a rat model of colorectal cancer. J Pharm Sci. 2013;102:2056–67.

    Article  CAS  PubMed  Google Scholar 

  17. Kobuchi S, Kuwano S, Imoto K, et al. A predictive biomarker for altered 5-fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer. Biopharm Drug Dispos. 2013;34:365–76.

    CAS  PubMed  Google Scholar 

  18. Buchel B, Rhyn P, Schurch S, et al. LC-MS/MS method for simultaneous analysis of uracil, 5,6-dihydrouracil, 5-fluorouracil and 5-fluoro-5,6-dihydrouracil in human plasma for therapeutic drug monitoring and toxicity prediction in cancer patients. Biomed Chromatogr. 2013;27:7–16.

    Article  PubMed  Google Scholar 

  19. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacomet Syst Pharmacol. 2013;17:e38.

    Article  Google Scholar 

  20. Chen J, Lu Q, Balthasar JP. Mathematical modeling of topotecan pharmacokinetics and toxicodynamics in mice. J Pharmacokinet Pharmacodyn. 2007;34:829–47.

    Article  PubMed  Google Scholar 

  21. Gao W, Jusko WJ. Modeling disease progression and rosiglitazone intervention in type 2 diabetic Goto-Kakizaki rats. J Pharmacol Exp Ther. 2012;341:617–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Friberg LE, Henningsson A, Maas H, et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20:4713–21.

    Article  PubMed  Google Scholar 

  23. Fuse E, Takai K, Okuno K, et al. Hepatic extraction ratio of 5-fluorouracil in rats. Dose dependence and effect of uracil and interleukin-2. Biochem Pharmacol. 1996;52:561–8.

    Article  CAS  PubMed  Google Scholar 

  24. Jarugula VR, Lam SS, Boudinot FD. Nonlinear pharmacokinetics of 5-fluorouracil in rats. J Pharm Sci. 1997;86:756–8.

    Article  CAS  PubMed  Google Scholar 

  25. van Kuilenburg AB, Maring JG. Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients. Pharmacogenomics. 2013;14:799–811.

    Article  PubMed  Google Scholar 

  26. Naguib FN, el Kouni MH, Cha S. Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res. 1985;45:5405–12.

    CAS  PubMed  Google Scholar 

  27. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol. 1988;6:1653–64.

    Article  CAS  PubMed  Google Scholar 

  28. Kobuchi S, Ito Y, Nakano Y, et al. Population pharmacokinetic modelling and simulation of 5-fluorouracil incorporating a circadian rhythm in rats. Xenobiotica. 2016;46:597–604.

    Article  CAS  Google Scholar 

  29. Baker SD, Verweij J, Rowinsky EK, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. J Natl Cancer Inst. 2002;94:1883–8.

    Article  CAS  PubMed  Google Scholar 

  30. Fety R, Rolland F, Barberi-Heyob M, et al. Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas. Clin Cancer Res. 1998;4:2039–45.

    CAS  PubMed  Google Scholar 

  31. Undevia SD, Gomez-Abuin G, Ratain MJ. Pharmacokinetic variability of anticancer agents. Nat Rev Cancer. 2005;5:447–58.

    Article  CAS  PubMed  Google Scholar 

  32. Jiang H, Lu J, Ji J. Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol. 2004;141:616–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ait-Oudhia S, Scherrmann JM, Krzyzanski W. Simultaneous pharmacokinetics/pharmacodynamics modeling of recombinant human erythropoietin upon multiple intravenous dosing in rats. J Pharmacol Exp Ther. 2010;334:897–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Woo S, Jusko WJ. Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos. 2007;35:1672–8.

    Article  CAS  PubMed  Google Scholar 

  35. Woo S, Krzyzanski W, Jusko WJ. Target-mediated pharmacokinetic and pharmacodynamic model of recombinant human erythropoietin (rHuEPO). J Pharmacokinet Pharmacodyn. 2007;34:849–68.

    Article  CAS  PubMed  Google Scholar 

  36. Bender BC, Schaedeli-Stark F, Koch R, et al. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2012;70:591–601.

    Article  CAS  PubMed  Google Scholar 

  37. Chalret du Rieu Q, Fouliard S, Jacquet-Bescond A, et al. Application of hematological toxicity modeling in clinical development of abexinostat (S-78454, PCI-24781), a new histone deacetylase inhibitor. Pharm Res. 2013;30:2640–53.

    Article  CAS  PubMed  Google Scholar 

  38. Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs. 2012;30:833–45.

    Article  CAS  PubMed  Google Scholar 

  39. Segura C, Bandrés E, Trocóniz IF, et al. Hematological response of topotecan in tumor-bearing rats: modeling of the time course of different cellular populations. Pharm Res. 2004;21:567–73.

    Article  CAS  PubMed  Google Scholar 

  40. Soto E, Staab A, Tillmann C, et al. Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development. Cancer Chemother Pharmacol. 2010;66:785–95.

    Article  CAS  PubMed  Google Scholar 

  41. Zandvliet AS, Schellens JH, Dittrich C, et al. Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin. Br J Clin Pharmacol. 2008;66:485–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Shinji Kobuchi, Yukako Ito & Toshiyuki Sakaeda

Authors
  1. Shinji Kobuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukako Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshiyuki Sakaeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinji Kobuchi.

Ethics declarations

Funding

This study was supported in part by a Grant-in-Aid for Scientific Research (C) (No. 24590223) and a Grant-in-Aid for Young Scientists (B) (No. 15K18937) from MEXT (Ministry of Education, Culture, Sports, Science and Technology) of Japan.

Conflict of interest

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

Ethical approval

The experimental design was approved by an institutional review board prior to performing the research and all animal protocols were conducted in accordance with the Kyoto Pharmaceutical University Guidelines for Animal Experimentation.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 381 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kobuchi, S., Ito, Y. & Sakaeda, T. Population Pharmacokinetic–Pharmacodynamic Modeling of 5-Fluorouracil for Toxicities in Rats. Eur J Drug Metab Pharmacokinet 42, 707–718 (2017). https://doi.org/10.1007/s13318-016-0389-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-016-0389-3

Keywords

Search

Navigation