Cytochrome P450 2C19 (CYP2C19)/ Plavix Sensitivity Test

Clinical Usage

  • Assess the likelihood of a reduced or enhanced response to clopidogrel (plavix), which is converted to its active form by CYP2C19.  Results of this test will identify patients that may not respond to clopidogrel, who will benefit from an alternate therapy.
  • Assess the probability of a reduced or enhanced response to pain medications that are metabolized by CYP2C19.
  • Determine the genotype of individuals with a personal or family history of adverse drug reactions to medications metabolized by CYP2C19.

Background Information

CYP2C19 acts on 5 – 10% of drugs currently prescribed.  CYP2C19 is a metabolizing enzyme that acts on clopidogrel (Plavix), some pain medications, and a variety of other drugs.  The efficacy and safety of these drugs can vary dramatically among individuals, and much of this variation is due to genetic differences in metabolic activity. 
CYP2C19 is a member of the cytochrome P450 enzymes located mainly in the liver, intestine and kidney.  A large number of variants caused by single nucleotide polymorphisms (SNPs) in the CYP2C19 gene affect the activity of the enzyme.  The most common variants that affect CTP2C19 activity are tested.
The FDA has issued a Drug Safety Communication that Plavix (clopidogrel) has reduced effectiveness in patients who are poor metabolizers of the drug.  Healthcare professionals are advised to consider alternate anti-platelet medications or alternative doses of Plavix for individuals who are poor metabolizers. Poor metabolizers are identified by determination of the CYP2C19 genotype.  
Platelets play a major role in atherothrombolic complications by participating in the formation of unwanted blood clots.  Clopidogrel (Plavix) keeps the platelets from coagulating (clotting). CYP2C19 converts clopidogrel to its active form.  CYP2C19 poor metabolizers are at risk for therapeutic failure when administered clopidogrel.
Pain medications that are substrates for CYP2C19 (methadone, meperidine) may have altered effectiveness for patients who are not normal CYP2C19 metabolizers.  Individuals with reduced or enhanced CYP2C19  metabolic activity may require altered doses for therapeutic efficacy and safety.

Gene Information

The CYP2C19 gene is located on the long (q) arm of chromosome 10 at position 24.  More precisely, the CYP2C19 gene is located from base pair 94,762,705 to base pair 94,852,913 on chromosome 10.

Population Information

Test Method

These assays were developed using CLSI guidelines.  Control DNA samples of known genotype are tested together with each patient sample to ensure correct results.  Genomic DNA is extracted from the submitted buccal swab sample and subjected to real time polymerase chain reaction (real time PCR).  The following CYP2C19 alleles were tested: *2, *3, *4, *5, *7, *8, *17.  The wild type or normal allele (*1) was assigned by default if none of the variant alleles were detected.  

Specimen

Collection

  • Buccal swab

Rejection Criteria

  • Buccal swab:

i. Physical damage
ii. Specimen appears to have microbial contamination or other visible contamination
iii. The name on the tube does not match the name on the paperwork.
iv. It is older than 10 days.

Interpretation

There are 4 phenotypic categories for CYP2C19:  Normal (extensive) Metabolizer, Intermediate Metabolizer, Poor Metabolizer, and Ultrarapid Metabolizer.  

CPT Code

81225

Test Limitations

The detection of genetic variants does not replace the need for therapeutic drug monitoring or other appropriate clinical monitoring by the health care provider.  Additional mutations for the tested genes that are not described in the methodology section will not be detected.  CYP2C19 metabolism is also influenced by concomitant medications, inhibitors, inducers, diet and various disease states.  These tests were developed and the performance characteristics were determined by MDL.  The CYP2C19 test has not been cleared or approved by the US Food and Drug Administration.  The FDA has determined that such approval is not necessary.

References

1. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. U.S. Food and Drug Administration. (March 2010).
2. Fefer P, Matetzky S.  The genetic basis of platelet responsiveness to clopidogrel.  A critical review of the literature.  Thromb Haemost.  106:  203-211.  2011
3. Gurbel PA, Tantry US.  Clopidogrel response variability and the adent of personalized antiplatelet therapy.  A bench to bedside journey.  Thromb Haemost.  106:  265-271.  2011
4. Kitzmiller JP, Groen DK, Phelps MA, Sadee W.  Pharmacogenomic Testing:  Relevance in Medical Practice.  Cleveland Clinic J of Medicine.  78 (4): 243 – 257.  2011
5. Gardiner SJ, Begg EJ.  Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice.  Pharmacol. Rev.  58(3): 521 – 590.  2006
6. Ma Q, Lu AYH.  Pharmacogenetics, Pharmacogenomics, and Individualized Medicine.  Pharmacol. Rev.  63: 437-459.  2011
7. Mega JL, et al.  Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated with Clopidogrel   Predominantly for PCI:  A Meta-Analysis.  JAMA  304(16): 1821 – 1830.   2010
8. Samer CF Lorenzini KI, Rollason V, Daali Y, Desmeules JA.  Applications of CYP450 Testing in the Clinical Setting.  Mol Diagn Ther 17: 165-184.  2013.
9. Scott SA, Sangkul K, Gardner EE, et al.  Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2C19 (CYP2C19) genotype and clopidogrel therapy.  Clin. Pharmacol. Ther.  90(2): 328-332.   2011
10. Strom CM, Goos D, Crosle B, Zhang K, Buller-Burkle A, Jarvis M, Quan F, Peng M, Su W.  Testing for variants in CYP2C19:  Population frequencies and testing experience in a clinical laboratory.  Genet Med  14(1): 95-100.   2012