Dutch Pharmacogenetics Working Group Guideline for CYP2C9, HLA-A and HLA-B Gene-Drug Interactions with Antiepileptic Drugs

Background

Pharmacogenetics (PGx) studies how genetic variations affect individual drug responses, aiming to guide drug selection and dosing, optimize drug therapy, prevent adverse drug reactions, and achieve safer and more cost-effective drug treatment. Although pharmacogenetics is widely recognized in the global medical field, its application in daily clinical practice still faces challenges.

To help clinicians implement pharmacogenetics, the Royal Dutch Pharmacists Association (KNMP) established the Dutch Pharmacogenetics Working Group (DPWG) in 2005. The DPWG’s goal is to develop pharmacogenetic-guided dosing recommendations based on systematic literature reviews and integrate these recommendations into computerized drug prescription, dispensing, and automated drug monitoring systems. The dual purpose of DPWG guidelines is to provide information needed to translate PGx test results into predicted phenotypes and to guide the programming of treatment recommendations in local clinical decision support systems.

Paper Overview

This paper was written by Lisanne E. N. Manson, Marga Nijenhuis, Bianca Soree, and others, affiliated with Leiden University Medical Center, Royal Dutch Pharmacists Association, University of Groningen, and other institutions. It was published online in the European Journal of Human Genetics on April 3, 2024, aiming to introduce gene-drug interactions related to antiepileptic drugs, especially the interactions between CYP2C9 gene and phenytoin, HLA-A gene and carbamazepine, and HLA-B gene with carbamazepine, lamotrigine, oxcarbazepine, and phenytoin.

Research Details

Workflow

The study adopted a systematic review method to review gene-drug interactions between CYP2C9, HLA-A, and HLA-B genes and antiepileptic drugs, and proposed drug therapy recommendations.

First, the researchers reviewed background knowledge of these genes and drugs. The CYP2C9 gene mainly affects the metabolism of phenytoin, while HLA-A and HLA-B alleles are associated with skin adverse reactions related to carbamazepine, lamotrigine, oxcarbazepine, and phenytoin. In particular, HLA-B*15:02 carriers face a higher risk of severe skin adverse reactions when using these drugs.

The study systematically reviewed evidence of relevant gene-drug interactions through literature searches and provided detailed descriptions of drug therapy recommendations. The review process included literature screening, abstract compilation, and recommendation development, with all literature grading and clinical relevance scoring collectively discussed and decided by DPWG members.

Main Results

CYP2C9 and Phenytoin:

The study found that polymorphisms of the CYP2C9 gene may lead to reduced enzyme activity, thereby increasing plasma concentrations of phenytoin and the risk of adverse reactions. For example, genotypes such as CYP2C9*1/*3, *1/*2, *2/*2, *2/*3, and *3/*3 all showed increased adverse reactions to phenytoin. Therefore, for these variant genotype groups, DPWG recommends reducing the daily dose, using 70-75% or 40-50% of the standard dose, respectively.

HLA and Antiepileptic Drugs:

Specific alleles of HLA genes, such as HLA-B*15:02, are associated with a significant increase in severe drug adverse reactions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by phenytoin, carbamazepine, lamotrigine, and oxcarbazepine. These reactions usually occur within the first three months of drug use. Therefore, DPWG recommends choosing alternative drugs for patients carrying HLA-B*15:02 when possible. For patients carrying HLA-A*31:01 and HLA-B*15:11 alleles, the balance between drug use and adverse reaction risk should also be weighed, and alternative drugs should be chosen if possible.

Carbamazepine, Oxcarbazepine, and Lamotrigine:

In patients carrying HLA-B*15:02, the risk of SJS/TEN caused by carbamazepine is significantly increased, even 10 times higher than the other three antiepileptic drugs. Therefore, DPWG strongly recommends avoiding the use of carbamazepine in these patients. Similarly, lamotrigine and oxcarbazepine also have an increased risk of skin adverse reactions, but to a lesser extent than carbamazepine. Therefore, if unavoidable, patients should be immediately alerted to report any rash.

Research Significance

This DPWG guideline, through systematic review and collective discussion, proposes personalized drug therapy recommendations based on gene-drug interactions, aiming to improve the safety and efficacy of drug therapy by preventing adverse drug reactions. Its clinical significance lies in: 1. Improving clinical drug safety: Guide drug selection and dose adjustment through personalized genetic testing to reduce the risk of adverse drug reactions. 2. Guiding clinicians: Provide specific drug therapy recommendations and clinical decision support system text to make the interpretation and application of genetic test results more convenient. 3. Promoting drug monitoring system improvement: Integrate personalized medication recommendations into computerized prescription systems to improve automated drug monitoring levels.

Research Highlights

1. Solid evidence: The research ensures all recommendations have a solid theoretical and empirical basis through systematic review of a large amount of literature.
2. Strong practicality: DPWG’s recommendations have strong clinical operability and provide specific electronic prescription system pop-ups or viewing text for practical application by physicians and pharmacists.
3. Personalized medication: Guide individualized drug selection and dose adjustment through genetic testing to maximize efficacy while minimizing adverse reactions.

Value and Significance

Through this study, DPWG provides scientific and practical pharmacogenetic guidance to help clinicians better understand and apply individual genetic information to optimize drug therapy and improve patient medication safety and treatment efficacy. This research is not only significant for clinical practice but also provides valuable reference for future pharmacogenetic research and clinical guideline development.

Conclusion

The Dutch Pharmacogenetics Working Group, through systematic research and multidisciplinary collaboration, has proposed a detailed guideline for gene-drug interactions of antiepileptic drugs. These guidelines not only help prevent adverse drug reactions and improve the safety and efficacy of drug therapy but also promote the application of pharmacogenetics in clinical practice, providing important support for the development of personalized medicine.