Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 52, 2022 - Issue 7
75
Views
0
CrossRef citations to date
0
Altmetric
General Xenobiochemistry

Predictive marker for exposure-driven haematological toxicity of tegafur-uracil and proposed modified-dosage regimen by pharmacometric approach in rats

, &
Pages 697-706 | Received 16 Sep 2022, Accepted 28 Oct 2022, Published online: 22 Nov 2022
 

Abstract

  1. Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5‑fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required.

  2. Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts.

  3. Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively.

  4. Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.

Acknowledgments

All authors would like to acknowledge Prof. Toshiyuki Sakaeda of the Department of Pharmacokinetics, Kyoto Pharmaceutical University (Kyoto, Japan) for his research guidance and suggestions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.