What is the research supporting pharmacogenomic (PGx) testing?

From the Guidelines

Pharmacogenomic testing is strongly supported by recent research as a valuable tool in personalizing medication therapy, particularly for medications with known genetic influences on metabolism, as demonstrated by the 2022 study published in Genetics in Medicine 1.

Key Points

• The goal of clinical pharmacogenomic testing is to examine genetic variants associated with interindividual variability in pharmacology, including drug metabolism, as outlined in the 2022 study 1.
• Pharmacogenomic testing can help guide drug selection and dosing decisions, reducing adverse drug reactions and improving treatment efficacy, as supported by the evidence from the 2018 study in the American Journal of Kidney Diseases 1.
• Notable examples of pharmacogenomic testing include CYP2C19 testing for clopidogrel response, CYP2D6 testing for codeine and tamoxifen metabolism, and HLA-B15:02 and HLA-A31:01 testing before carbamazepine initiation.
• Research shows that pharmacogenomic-guided therapy can enhance medication adherence and reduce healthcare costs by preventing ineffective treatments and adverse events, as demonstrated by the 2022 study 1.

Implementation and Resources

• The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides evidence-based gene/drug clinical practice guidelines, as mentioned in the 2018 study 1.
• Publicly available resources, such as the Pharmacogenomic Knowledgebase (PharmGKB) and the Pharmacogene Variation (PharmVar) Consortium, support clinical pharmacogenomic testing, as outlined in the 2022 study 1.
• The FDA has published resource tables for pharmacogenomic biomarkers, including the "Table of Pharmacogenomic Biomarkers in Drug Labeling" and the "Table of Pharmacogenetic Associations", as mentioned in the 2022 study 1.

Clinical Utility

• Pharmacogenomic testing has the potential to improve patient outcomes and reduce morbidity and mortality by providing personalized medication therapy, as supported by the evidence from the 2022 study 1.
• The field continues to evolve with expanding evidence for additional drug-gene pairs, including SSRIs, antipsychotics, and pain medications, as demonstrated by the 2022 study 1.
• Implementation challenges remain, but research increasingly demonstrates the clinical utility of pharmacogenomic testing in real-life clinical practice, as supported by the 2018 study 1.

From the FDA Drug Label

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C92 and CYP2C93 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients. Patients carrying at least one copy of the CYP2C92 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C91 allele. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin CYP2C19 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 vivoplatelet aggregation assays, differ according to CYP2C19 genotype Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers.”

Pharmacogenomic testing is supported by research for warfarin and clopidogrel.

• Warfarin: Variants in the CYP2C9 and VKORC1 genes affect the dose requirements and bleeding risk.
• Clopidogrel: Variants in the CYP2C19 gene affect the formation of the active metabolite and antiplatelet effects. Key points:
• Genetic variants can affect the metabolism and efficacy of these drugs.
• Pharmacogenomic testing can help identify patients who may require dose adjustments or alternative treatments.
• CYP2C9 and VKORC1 genotypes are associated with warfarin dose requirements and bleeding risk.
• CYP2C19 genotype is associated with clopidogrel efficacy and platelet inhibition 2, 3.

From the Research

Benefits of Pharmacogenomic Testing

• Pharmacogenomic testing can help identify patients at increased risk for medication toxicity, poor response, or treatment failure, and inform drug therapy 4.
• It can optimize medicine prescribing and improve patient outcomes by tailoring treatment based on a patient's genetic profile 5.
• Pharmacogenomics can enhance patient care by enabling treatments tailored to genetic make-up and lowering the risk of serious adverse events 6.

Clinical Evidence and Implementation

• There are 132 pharmacogenomic dosing guidelines for 99 drugs, and pharmacogenomic information is included in 309 medication labels 6.
• Next-generation sequencing (NGS) is a cost-effective option for genotyping patients at many pharmacogenomic loci simultaneously, and guidelines for implementation of these data are available from organizations such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) 6.
• A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines 7.

Challenges and Limitations

• Clinical uptake of pharmacogenetic testing has been limited, and relatively few clinical practice guidelines provide a pharmacogenetic testing recommendation 7.
• Testing recommendations for the same gene-drug pair are often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization 7.
• Rates of genomic literacy remain low, resulting in a widening gap in knowledge translation to the patient 6.

Specific Gene-Drug Pairs

• Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered include CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines 7.
• Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase are mostly consistent across guidelines 7.