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Dutch pharmacogenetics working group (DPWG) guideline for the gene–drug interaction between UGT1A1 and irinotecan

European Journal of Human Genetics (2022)Cite this article

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A Correction to this article was published on 16 February 2023

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Abstract

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of the anti-cancer drug irinotecan to decrease the risk of severe toxicity, such as (febrile) neutropenia or diarrhoea. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1 encoded by the UGT1A1 gene) enzyme deficiency increases risk of irinotecan-induced toxicity. Gene variants leading to UGT1A1 enzyme deficiency (e.g. UGT1A1*6, *28 and *37) can be used to optimize an individual’s starting dose thereby preventing carriers from toxicity. Homozygous or compound heterozygous carriers of these allele variants are defined as UGT1A1 poor metabolisers (PM). DPWG recommends a 70% starting dose in PM patients and no dose reduction in IM patients who start treatment with irinotecan. Based on the DPWG clinical implication score, UGT1A1 genotyping is considered “essential”, indicating that UGT1A1 testing must be performed prior to initiating irinotecan treatment.

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Fig. 1: Irinotecan metabolism. Irinotecan and its metabolites are presented in rectangles.

Data availability

All data and material are either included in the supplementary information or publicly available (i.e. the published articles, PubMed). The guidelines and background information are available on the website of the Royal Dutch Pharmacists Association (KNMP) (Pharmacogenetic Recommendation Text. Available from: https://www.knmp.nl/).

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Funding

The U-PGx consortium received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 668353. The DPWG received funding from the Royal Dutch Pharmacists Association.

Author information

Author notes

  1. These authors contributed equally: Emma C. Hulshof, Maarten J. Deenen.

  2. These authors jointly supervised this work: Henk-Jan Guchelaar, Jesse J. Swen.

Authors and Affiliations

  1. Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands

    Emma C. Hulshof & Maarten J. Deenen

  2. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Emma C. Hulshof, Maarten J. Deenen, Henk-Jan Guchelaar & Jesse J. Swen

  3. Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands

    Marga Nijenhuis & Bianca Soree

  4. Pharmacy Boterdiep, Groningen, The Netherlands

    Nienke J. de Boer-Veger

  5. Pharmacy De Katwijkse Apotheek, Katwijk, The Netherlands

    Anne-Marie Buunk

  6. Department of Public Health and Primary Care (PHEG), Leiden University Medical Centre, Leiden, The Netherlands

    Elisa J. F. Houwink

  7. National eHealth Living Lab (NELL), Leiden, The Netherlands

    Elisa J. F. Houwink

  8. Department of Clinical Pharmacy, Wilhelmina Hospital, Assen, The Netherlands

    Arne Risselada

  9. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Gerard A. P. J. M. Rongen

  10. Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands

    Gerard A. P. J. M. Rongen

  11. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ron H. N. van Schaik

  12. Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Daan J. Touw

  13. Department of PharmacoTherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

    Daan J. Touw

  14. Department of Clinical Chemistry, St. Jansdal Hospital, Harderwijk, The Netherlands

    Jan van der Weide

  15. Department of Psychiatry, Parnassia Group, Amsterdam, The Netherlands

    Roos van Westrhenen

  16. Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands

    Roos van Westrhenen

  17. Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, London, UK

    Roos van Westrhenen

  18. Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    Vera H. M. Deneer

  19. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Vera H. M. Deneer

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Contributions

ECH and MJD drafted the manuscript. JJS and HJG supervised drafting of the manuscript and contributed to conceiving the work and interpretation of the results. MN performed most of the literature searches and article summaries, and suggested clinical decision support texts. BS had the clinical decision support texts translated in English and published them. NBV, AB, EJHF, AR, GAR, RHNS, DT, JW, and RW contributed to conceiving the work and interpretation of the results. VHMD led the meetings in which the DPWG decided about the article summaries and clinical decision supports texts and contributed to conceiving the work and interpretation of the results. In addition, all authors revised the manuscript and approved the final version.

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Correspondence to Marga Nijenhuis.

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Hulshof, E.C., Deenen, M.J., Nijenhuis, M. et al. Dutch pharmacogenetics working group (DPWG) guideline for the gene–drug interaction between UGT1A1 and irinotecan. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01243-2

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