What is the role of pharmacogenetic testing in optimizing personalized drug therapy?

From the Guidelines

Pharmacogenetic testing is a crucial tool for optimizing drug therapy and should be considered before initiating medications with known genetic influences, as it can significantly reduce adverse drug reactions and improve therapeutic efficacy, as supported by the most recent study from 2022 1. The primary goal of pharmacogenetic testing is to examine genetic variants associated with interindividual variability in drug metabolism, which can explain some drug response phenotypes, including therapeutic failure, side effects, and nonstandard dosing.

• The testing process typically involves a simple cheek swab or blood sample, with results available within days to weeks depending on the laboratory.
• When implementing pharmacogenetic-guided therapy, clinicians should interpret results in conjunction with other clinical factors, including age, organ function, drug interactions, and comorbidities.
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides evidence-based gene/drug clinical practice guidelines, which can help clinicians make informed decisions about drug selection and dosing based on pharmacogenomic test results, as mentioned in the 2018 study 1.
• Additionally, publicly available resources such as the Pharmacogenomic Knowledgebase (PharmGKB) and the Pharmacogene Variation (PharmVar) Consortium can support clinical pharmacogenomic testing and provide valuable information on gene-drug associations and pharmacogenomic biomarkers, as discussed in the 2022 study 1.
• While pharmacogenetic testing represents an upfront cost, it can provide lifetime value since genetic information remains unchanged and can guide multiple medication decisions throughout a patient's life, potentially reducing overall healthcare costs through fewer adverse events and medication adjustments, as highlighted in the 2008 study 1. Key considerations for pharmacogenetic testing include:
• The incremental clinical benefit of the test over existing methodologies
• The magnitude of the increased risk for an adverse event in the variant genotype group relative to the wild-type group
• The change in benefit that occurs from the drug in the variant group
• The balance between reducing adverse events and potentially exposing patients to a higher risk of other adverse outcomes.

From the FDA Drug Label

The CYP2C19 gene is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers.” Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers.

Pharmacogenetic Testing is a tool for personalized drug therapy optimization.

• Clopidogrel is metabolized to its active metabolite in part by CYP2C19.
• CYP2C19 poor metabolizers have decreased active metabolite exposure and diminished inhibition of platelet aggregation.
• Genetic testing can identify patients who are CYP2C19 poor metabolizers.
• Warfarin dose requirements can also be influenced by CYP2C9 and VKORC1 genotypes.
• Pharmacogenetic testing can help optimize drug therapy and reduce the risk of adverse events 2 3.

From the Research

Pharmacogenetic Testing for Personalized Drug Therapy Optimization

• Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment, improving treatment outcomes 4.
• Clinical practice guidelines recommend biomarker tests that have demonstrated clinical utility, meaning that testing improves treatment outcomes 4.
• Gene-drug pairs with established drug response associations and clinical actionability include CYP2C19-clopidogrel, CYP2D6-codeine, and TPMT-thiopurines 4.

Clinical Application of Pharmacogenomics

• Genetic polymorphisms significantly influence responses to warfarin and clopidogrel, with polymorphisms in CYP2C9 and VKORC1 affecting warfarin pharmacokinetics and pharmacodynamics 5, 6.
• Pharmacogenomic testing can help determine therapeutic warfarin doses and identify clopidogrel nonresponders who may benefit from alternative antiplatelet agents 5.
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) develops guidelines for gene-drug pairs, including CYP2C9 and VKORC1 genotypes and warfarin dosing 6.

Impact of Pharmacogenomic-Guided Pathways on Medication Changes and Hospital Admissions

• Pharmacogenomic testing has the potential to identify patients with genetic variants that put them at risk of adverse drug reactions and sub-optimal therapy, supporting safe medication management and reducing hospitalization 7.
• A systematic review and meta-analysis found that medication changes occurred significantly more frequently in the pharmacogenomic tested arm, and all-cause hospitalization occurred significantly less frequently in the pharmacogenomic tested arm than in the treatment-as-usual arm 7.
• Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation can optimize therapeutic response and reduce bleeding risk 8.