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Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity

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Abstract

Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment.

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Authors and Affiliations

  1. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Nikki de Rouw, Hieronymus J. Derijks & Rob ter Heine

  2. Department of Pharmacy, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

    Nikki de Rouw & Hieronymus J. Derijks

  3. Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

    Berber Piet & Michel M. van den Heuvel

Authors
  1. Nikki de Rouw
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  2. Berber Piet
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  3. Hieronymus J. Derijks
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  4. Michel M. van den Heuvel
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  5. Rob ter Heine
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Corresponding author

Correspondence to Nikki de Rouw.

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Funding

This research was supported by ZonMw, The Netherlands (Grant number: 848016010).

Conflicts of interest/competing interests

Drs. Nikki de Rouw, Dr. Hieronymus J. Derijks, Prof. Dr. Michel M. van den Heuvel and Dr. Rob ter Heine have nothing to disclose. Dr. Berber Piet reports membership of Advisory Boards of Takeda and Bristol Meyer Squibb and lecturer fees from Astra Zeneca and Pfizer, outside the submitted work.

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Author contributions

Manuscript writing, editing, and revisions: Drs. Nikki de Rouw, Dr. Berber Piet, Dr. Hieronymus J. Derijks, Prof. Dr. Michel M. van den Heuvel, and Dr. Rob ter Heine. All authors read and approved the final version.

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de Rouw, N., Piet, B., Derijks, H.J. et al. Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity. Drug Saf 44, 1271–1281 (2021). https://doi.org/10.1007/s40264-021-01135-2

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  • DOI: https://doi.org/10.1007/s40264-021-01135-2