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Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats

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Abstract

Purpose

Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats.

Methods

Rats were administered intravenous L-OHP, once a week for 4 weeks, at doses of 3, 5, or 8 mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4 weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period.

Results

The mean AUC0-∞ values for L-OHP were 0.4 ± 0.2, 2.4 ± 0.4, and 3.5 ± 0.9 ng h/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0-∞ values of 0.6 ± 0.2, 4.0 ± 1.0, and 14.1 ± 9.8 ng·h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8 mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8 mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters.

Conclusion

These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment.

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Acknowledgements

I would like to express the deepest appreciation to Professor Toshiyuki Sakaeda. Without his guidance and persistent help, this paper would not have been possible.

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Authors and Affiliations

  1. Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, 607-8412, Japan

    Yukako Ito, Shinji Kobuchi, Risa Shimizu & Yosuke Katsuyama

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  1. Yukako Ito
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  2. Shinji Kobuchi
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  3. Risa Shimizu
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  4. Yosuke Katsuyama
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Corresponding author

Correspondence to Yukako Ito.

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Funding

This study was supported by a Grant-in-Aid for Scientific Research (C) from JSPS KAKENHI, Grant number 15K08085.

Conflict of interest

Y. Ito declares that she has no conflict of interest. S. Kobuchi declares that he has no conflict of interest. R. Shimizu hat she has no conflict of interest. Y. Katsuyama that he has no conflict of interest.

Ethical approval

All animal protocols were approved by the Institutional Animal Care and Use Committee. Experiments were conducted in accordance with the Guidelines for Animal Experimentation, Kyoto Pharmaceutical University.

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Ito, Y., Kobuchi, S., Shimizu, R. et al. Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats. Cancer Chemother Pharmacol 81, 155–161 (2018). https://doi.org/10.1007/s00280-017-3485-4

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  • DOI: https://doi.org/10.1007/s00280-017-3485-4

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