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Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs

European Journal of Human Genetics (2024)Cite this article

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Abstract

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7–10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin “essential” for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine “beneficial”, as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

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Fig. 1: Overview of phenytoin metabolism and excretion.

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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 KNMP.nl [26] and will be available on PharmGKB.org.

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Acknowledgements

We want to thank Anna de Goede for performing the first systematic review for phenytoin and CYP2C9 in 2006 and Inge Holsappel for performing the systematic review for phenytoin and CYP2C9 in 2016.

Funding

This project has 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

Authors and Affiliations

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

    Lisanne E. N. Manson, Jesse J. Swen & Henk-Jan Guchelaar

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

    Marga Nijenhuis & Bianca Soree

  3. Pharmacy Boterdiep, Groningen, The Netherlands

    Nienke J. de Boer-Veger

  4. Pharmacy De Katwijkse Apotheek, Katwijk, The Netherlands

    Anne-Marie Buunk

  5. Department of Family Medicine, Mayo Clinic, Rochester, MN, USA

    Elisa J. F. Houwink

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

    Arne Risselada

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

    Gerard A. P. J. M. Rongen

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

    Gerard A. P. J. M. Rongen

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

    Ron H. N. van Schaik

  10. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Daan J. Touw

  11. Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

    Daan J. Touw

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

    Roos van Westrhenen

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

    Roos van Westrhenen

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

    Roos van Westrhenen

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

    Vera H. M. Deneer

  16. 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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  1. Lisanne E. N. Manson
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Contributions

LENM drafted the manuscript. MN performed most of the literature searches and article summaries and suggested clinical decision support texts. HJG supervised drafting of the manuscript and contributed to conceiving the work and interpretation of the results. BS had the clinical decision support texts translated in English and published them. NBV, AB, EJFH, AR, GAR, RHNS, JJS, DT, 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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Supplementary information

41431_2024_1572_MOESM1_ESM.docx

Supplementary Material: Details of the searches used to perform the literature review of gene-anti-epileptic drug interactions (dates, search terms, and article selection criteria)

41431_2024_1572_MOESM2_ESM.docx

Supplementary table 1. Literature review of CYP2C9-phenytoin supporting the therapeutic guideline to change the dose in CYP2C9 intermediate and poor metabolisers

41431_2024_1572_MOESM3_ESM.docx

Supplementary table 2. Literature review of HLA-phenytoin supporting the therapeutic guideline of avoiding phenytoin if an alternative is available in HLA-B*15:02 carriers.

Supplementary table 3. Literature review of HLA-carbamazepine

41431_2024_1572_MOESM5_ESM.docx

Supplementary table 4. Literature review of HLA-lamotrigine interactions to support the therapeutic guideline of avoiding lamotrigine if an alternative is available in HLA-B*15:02 carriers.

41431_2024_1572_MOESM6_ESM.docx

Supplementary table 5. Literature review of HLA-oxcarbazepine interactions to support the therapeutic guideline of avoiding oxcarbazepine if an alternative is available in HLA-B*15:02 carriers.

Supplementary table 6. The most important CYP2C9 alleles and their predicted enzyme activity

Supplementary table 7. Ethnic variation in prevalence of genotypes# and allele frequencies for CYP2C9.

Supplementary Table 8: Translation of genotype to pharmacogenetic contraindication

Supplementary table 9. Ethnic variation in carrier frequency of HLA-A*31:01, HLA-B*15:02 and HLA-B*15:11.

Supplementary table 10. Dutch Pharmacogenetics Working Group (DPWG) Guideline for CYP2C9 and phenytoin

Supplementary table 11. Dutch Pharmacogenetics Working Group (DPWG) Guideline for HLA and phenytoin

Supplementary table 12. Dutch Pharmacogenetics Working Group (DPWG) Guideline for HLA and carbamazepine

Supplementary table 13. Dutch Pharmacogenetics Working Group (DPWG) Guideline for HLA and lamotrigine

Supplementary table 14. Dutch Pharmacogenetics Working Group (DPWG) Guideline for HLA and oxcarbazepine

41431_2024_1572_MOESM16_ESM.docx

Supplementary table 15. Suggested clinical decision support texts for various health care professionals for CYP2C9 – phenytoin

41431_2024_1572_MOESM17_ESM.docx

Supplementary table 16. Suggested clinical decision support texts for various health care professionals for HLA-B*15:02– phenytoin

41431_2024_1572_MOESM18_ESM.docx

Supplementary table 17. Suggested clinical decision support texts for various health care professionals for HLA-A*31:01, HLA-B*15:02 and HLA-B*15:11 – carbamazepine

41431_2024_1572_MOESM19_ESM.docx

Supplementary table 18. Suggested clinical decision support texts for various health care professionals for HLA-B*15:02– lamotrigine

41431_2024_1572_MOESM20_ESM.docx

Supplementary table 19. Suggested clinical decision support texts for various health care professionals for HLA-B*15:02– oxcarbazepine

Supplementary table 20. The Clinical Implication Score

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Manson, L.E.N., Nijenhuis, M., Soree, B. et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01572-4

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