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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Swen JJ, Huizinga TW, Gelderblom H, de Vries EGE, Assendelft WJJ, Kirchheiner J, et al. Translating pharmacogenomics: challenges on the road to the clinic. PLoS Med. 2007;4:e209.
van Westrhenen R, Aitchison KJ, Ingelman-Sundberg M, Jukić MM. Pharmacogenomics of antidepressant and antipsychotic treatment: how far have we got and where are we going? Front Psychiatry. 2020;11:94.
Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharm Ther. 2011;89:662–73.
Swen JJ, Nijenhuis M, van Rhenen M, de Boer‐Veger NJ, Buunk AM, Houwink EJF, et al. Pharmacogenetic information in clinical guidelines: the European perspective. Clin Pharmacol Ther. 2018;103:795–801.
European Association for Clinical Pharmacology and Therapeutics (EACPT). 2017. https://www.eacpt.eu/.
European Association of Hospital Pharmacists (EAHP). 2017. https://www.eahp.eu/.
Beunk L, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, Guchelaar HJ, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet. 2023;32:278–85.
Brouwer JMJL, Nijenhuis M, Soree B, Guchelaar HJ, Swen JJ, van Schaik RHN, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet. 2022;30:1114–20.
Hulshof EC, Deenen MJ, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between UGT1A1 and irinotecan. Eur J Hum Genet. 2023;31:982–7.
Lunenburg CATC, van der Wouden CH, Nijenhuis M, Crommentuijn-van Rhenen MH, de Boer-Veger NJ, Buunk AM, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet. 2020;28:508–17.
Matic M, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, Houwink EJF, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone). Eur J Hum Genet. 2022;30:1105–13.
Nijenhuis M, Soree B, Jama WOM, de Boer-Veger NJ, Buunk AM, Guchelaar HJ, et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2D6 and COMT with atomoxetine and methylphenidate. Eur J Hum Genet. 2023;31:1364–70.
van der Pol KH, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, Guchelaar HJ, et al. Dutch Pharmacogenetics Working Group guideline for the gene-drug interaction of ABCG2, HLA-B and Allopurinol, and MTHFR, folic acid and methotrexate. Eur J Hum Genet. 2024;32:155–62.
Bloch KM, Sills GJ, Pirmohamed M, Alfirevic A. Pharmacogenetics of antiepileptic drug-induced hypersensitivity. Pharmacogenomics. 2014;15:857–68.
Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology. 2005;64:1134–8.
GlaxoSmithKline BV. Lamictal (lamotrigine): full prescribing information. GlaxoSmithKline; 2009.
US Food and Drug Administration. Official drug label: Trileptal (oxcarbazepine). 2009.
NCBI. CYP2C9 cytochrome P450 family 2 subfamily C member 9 [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/1559.
Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, et al. Recommendations for clinical CYP2C9 genotyping allele selection: a joint recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn. 2019;21:746–55.
Genbank. Homo sapiens MHC class I antigen (HLA) mRNA, HLA-A*3101 allele, complete cds. https://www.ncbi.nlm.nih.gov/nuccore/M84375.1.
Genbank. Homo sapiens mRNA for HLA-B*1502, complete cds. https://www.ncbi.nlm.nih.gov/nuccore/D50293.1.
Genbank. Homo sapiens mRNA for HLA-B*1511, complete cds. https://www.ncbi.nlm.nih.gov/nuccore/D50294.1.
Whirl-Carrillo M, Huddart R, Gong L, Sangkuhl K, Thorn CF, Whaley R, et al. An evidence-based framework for evaluating pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2021;110:563–72.
Thorn CF, Whirl-Carrillo M, Leeder JS, Klein TE, Altman RB. PharmGKB summary: phenytoin pathway. Pharmacogenet Genomics. 2012;22:466–70.
Swen J, Wilting I, de Goede A, Grandia L, Mulder H, Touw D, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther. 2008;83:781–7.
Royal Dutch Pharmacists Association (KNMP): pharmacogenetic recommendation text. 2023. https://www.knmp.nl/.
Karamperis K, Koromina M, Papantoniou P, Skokou M, Kanellakis F, Mitropoulos K, et al. Economic evaluation in psychiatric pharmacogenomics: a systematic review. Pharmacogenomics J. 2021;21:533–41.
Simeonidis S, Koutsilieri S, Vozikis A, Cooper DN, Mitropoulou C, Patrinos GP. Application of economic evaluation to assess feasibility for reimbursement of genomic testing as part of personalized medicine interventions. Front Pharm. 2019;10:830.
Bank P, Caudle K, Swen J, Gammal R, Whirl‐Carrillo M, Klein T, et al. Comparison of the guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Clin Pharmacol Ther. 2018;103:599–618.
Abdullah-Koolmees H, van Keulen AM, Nijenhuis M, Deneer VHM. Pharmacogenetics guidelines: overview and comparison of the DPWG, CPIC, CPNDS, and RNPGx guidelines. Front Pharm. 2020;11:595219.
Karnes JH, Rettie AE, Somogyi AA, Huddart R, Fohner AE, Formea CM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and HLA-B genotypes and phenytoin dosing: 2020 update. Clin Pharmacol Ther. 2021;109:302–9.
Phillips EJ, Sukasem C, Whirl‐Carrillo M, Müller DJ, Dunnenberger HM, Chantratita W, et al. Clinical Pharmacogenetics Implementation Consortium guideline for HLA genotype and use of carbamazepine and oxcarbazepine: 2017 update. Clin Pharmacol Ther. 2018;103:574–81.
Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al. Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia. 2014;55:496–506.
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
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
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
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.
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
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41431-024-01572-4