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

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.

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Authors

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.

Corresponding author

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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