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Dutch pharmacogenetics working group (DPWG) guideline for the gene-drug interaction of CYP2D6 and COMT with atomoxetine and methylphenidate

European Journal of Human Genetics volume 31, pages 1364–1370 (2023)Cite this article

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Abstract

Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being “potentially beneficial” for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.

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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 [9] and will be available on PharmGKB.org.

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Acknowledgements

We want to thank Anna de Goede and Leonora Grandia for summarising atomoxetine articles in 2006, and Mandy van Rhenen for performing the literature searches for methylphenidate and CYP2D6 and for clonidine in 2016. In addition, we want to thank Leonora Grandia for initiating the pharmacogenetics subject within the Royal Dutch Pharmacists Association and leading this until May 2012.

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

    Marga Nijenhuis, Bianca Soree & Wafa O. M. Jama

  2. Pharmacy Boterdiep, Groningen, The Netherlands

    Nienke J. de Boer-Veger

  3. Pharmacy De Katwijkse Apotheek, Katwijk, The Netherlands

    Anne Marie Buunk

  4. Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Henk-Jan Guchelaar & Jesse J. Swen

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

    Elisa J. F. Houwink

  6. Department of Family Medicine, Mayo Clinic, Rochester, MIN, USA

    Elisa J. F. Houwink

  7. Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Gerard A. Rongen

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

    Gerard A. Rongen

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

    Ron H. N. van Schaik

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

    Daan Touw

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

    Jan van der Weide

  12. Parnassia Psychiatric Institute/PsyQ, Amsterdam, The Netherlands

    Roos van Westrhenen

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

    Roos van Westrhenen

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

    Roos van Westrhenen

  15. Department of Clinical Pharmacy, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Centre 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

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

    Arne Risselada

Authors
  1. Marga Nijenhuis
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Contributions

MN performed most of the literature searches and article summaries, suggested clinical decision support texts, and drafted the manuscript. AR 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. WOMJ collected data required for the CYP2D6 genotype-phenotype translation for implementation into clinical decision support systems. NBV, AB, HJG, EJHF, GAR, RHNS, JJS, 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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The authors declare no competing interests.

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Supplementary information

Supplementary Material 1: Gene: cytochrome P450 2D6 (CYP2D6)

Supplementary Material 2: Procedure of choosing gene-drug combinations and details of the searches

Supplementary Table 1: Literature review of CYP2D6-atomoxetine interactions

Supplementary Table 2: Literature review for CYP2D6-methylphenidate

Supplementary Table 3: Literature review for COMT-methylphenidate

41431_2022_1262_MOESM6_ESM.docx

Supplementary Table 4A-C: CYP2D6 alleles stratified by predicted enzyme activity and ethnic variation in CYP2D6 alleles and phenotypes

Supplementary Table 5A/B: Genotype to predicted phenotype translation for CYP2D6 and COMT to be programmed

Supplementary Table 6: Ethnic variation in COMT allele and predicted phenotype frequency.

41431_2022_1262_MOESM9_ESM.docx

Supplementary Table 7: CYP2D6 and atomoxetine: the therapeutic recommendation and its rationale, and the kinetic and clinical consequences

41431_2022_1262_MOESM10_ESM.docx

Supplementary Table 8: CYP2D6 and methylphenidate: the conclusion and its rationale, and the kinetic and clinical consequences

41431_2022_1262_MOESM11_ESM.docx

Supplementary Table 9: COMT and methylphenidate: the conclusion and its rationale, and the kinetic and clinical consequences

Supplementary Table 10: Suggested clinical decision support texts for atomoxetine

Supplementary Table 11: Suggested clinical decision support texts for methylphenidate and CYP2D6

Supplementary Table 12: Suggested clinical decision support texts for methylphenidate and COMT

Supplementary Table 13: Suggested clinical decision support texts for clonidine

Supplementary Table 14: The clinical implication score of CYPD6-atomoxetine is “potentially beneficial”

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Nijenhuis, M., Soree, B., Jama, W.O.M. 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 31, 1364–1370 (2023). https://doi.org/10.1038/s41431-022-01262-z

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