Cytochrome p450 Genotyping
Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018
Drug efficacy and toxicity vary substantially by individual. Because drugs and doses are typically adjusted, if needed, by trial and error, clinical consequences may include a prolonged time to optimal therapy. Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body's response to drugs. It has been investigated as a tool in predicting therapeutic failures or severe adverse drug reactions. Pharmacogenetics tests for DNA sequence variations in drug metabolizing enzymes, drug receptors, and drug transporters. Potentially the identification of significant polymorphisms could be used to improve efficacy and safety of drug choice and /or dosage.
The cytochrome P450 (CYP450) family is a major subset of all drug-metabolizing enzymes. Several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. CYP2D6 metabolizes approximately 25% of all clinically used medications (e.g., dextromethorphan, beta blockers, antiarrhythmics, antidepressants and morphine derivatives). CYP450 enzyme genes can have distinct variations which can affect individual capability to metabolize specific drugs. CYP450 genotyping has been proposed as a way to direct early selection of the most effective drug or dose to avoid significant adverse events and speed the process of achieving a therapeutic dose.
Diagnostic genotyping tests for certain CYP450 enzymes are available. Several testing kits for CYP450 genotyping have been cleared by FDA. Test kits specific for the CTP2D6 include the AmpliChip® (33 CYP2D6 alleles) and the xTAG® CYP2D6 kit.
Test kits for CYP2C19 include the INFINITI™ CYP2C19 Assay, the Verigene CYP2C19 Nucleic Acid Test, and the Spartan RX® CYP2C19 testing system. Several manufacturers market diagnostic panel tests for genotyping that include multiple CYP450 genes, such as the YouScript Panel (CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4, and CYP3A5). Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the PersonaGene Genetic Panels.
Cytochrome P450 (CYP2D6) genotyping to determine drug metabolizer status is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Cytochrome P450 (CYP450) genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the following drugs is considered investigational:
Selection or dosing of clopidogrel
Selection or dosing of selective serotonin reuptake inhibitors (SSRIs)
Selection or dosing of selective norepinephrine reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors
Selection or dosing of tricyclic antidepressants
Selection or dosing of antipsychotic drugs
Selection or dosing of codeine
Dosing of efavirenz and other antiretroviral therapies for HIV (human immunodeficiency virus) infection
Dosing of immunosuppressants for organ transplantation
Selection or dosing of beta blockers
Dosing and management of anti-tuberculosis medications
Selection or dosing of tamoxifen
Cytochrome P450 (CYP2C19) genotyping to determine drug metabolizer status in the treatment of Helicobacter pylori is considered investigational.
The use of genetic testing panels that include multiple CYP450 mutations is considered investigational.
Genotyping of Cytochrome P450 (CYP2D6) to determine drug metabolizer status is considered medically appropriate if ANY ONE of the following are met:
Individual with Gaucher disease being considered for treatment with eliglustat
Individual with Huntington’s disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day
Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.
Individuals with genetic variants of cytochrome P450 have a decreased ability to metabolize clopidogrel, but the impact on clinically meaningful outcomes is uncertain. While genotyping appears in some studies to be helpful in identifying individuals at higher risk of treatment failure and may be useful in selected individuals, more information is needed to refine optimal use of testing and to better understand the relative merit of management options.
The evidence for cytochrome P450 genotyping in individuals with various clinical conditions undergoing or being considered for treatment with a drug metabolized by CYP450 enzymes is insufficient to determine the effects of the technology on health outcomes.
Ahern, T., Hertz, D., Damkier, P., Eilertsen, B., Hamilton-Dutoit, S., Rae, J., et al. (2017). Cytochrome P-450 2D6 (CYP2D6) genotype and breast cancer recurrence in tamoxifen-treated patients: evaluating the importance of loss of heterozygosity. American Journal of Epidemiology, 185 (2), 75-85. Abstract retrieved November 20, 2017 from PubMed database.
American College of Cardiology Foundation/American Heart Association. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. Retrieved February 2, 2016 from http://content.onlinejacc.org.
American College of Cardiology Foundation/American Heart Association. (2010). ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”. Retrieved September 27, 2012 from http://circ.ahajournals.org.
BlueCross BlueShield Association. Evidence Positioning System. (7:2018). Genotype-guided tamoxifen treatment (2.04.51). Retrieved September 27, 2018 from http://www.evidencepositioningsystem.com. (17 articles and/or guidelines reviewed)
BlueCross BlueShield Association. Evidence Positioning System. (6:2018). Cytochrome p450 genotyping guided treatment strategy (2.04.38). Retrieved September 27, 2018 from http://www.evidencepositioningsystem.com. (21 articles and/or guidelines reviewed)
BlueCross BlueShield Association. Evidence Positioning System. (6:2018). Genetic testing for diagnosis and management of mental health conditions. (2.04.110). Retrieved September 27, 2018 from http://www.evidencepositioningsystem.com. (71 articles and/or guidelines reviewed)
Bykov, K., Schneeweiss, S., Glynn, R., Mittleman, M., Bates, D., & Gagne, J. (2017). Updating the evidence of the interaction between clopidogrel and CYP2C19-inhibiting selective serotonin reuptake inhibitors: a cohort study and meta-analysis. Drug Safety, 40 (10), 923-932. Abstract retrieved November 20, 2017 from PubMed database.
Espadaler, J., Tuson, M., Lopez-Ibor, J., Lopez-Ibor, F., and Lopez-Ibor, M. (2017, August) Pharmacogenetic testing for the guidance of psychiatric treatment: a multicenter retrospective analysis. CNS Spectrums, 22 (4), 315-324. (Level 4 evidence)
eviCore® healthcare (2019, January) Lab Management Program: Pharmacogenetic testing for drug toxicity and response. Retrieved September 27, 2018 from www.evicore.com (10 articles and/or guidelines reviewed)
Huang, B., Cui, D., & Zhao, X. (2017). Effect of cytochrome P450 2C19*17 allelic variant on cardiovascular and cerebrovascular outcomes in clopidogrel-treated patients: a systematic review and meta-analysis. Journal of Research in Medical Sciences, 22, 109. (Level 1 evidence)
National Comprehensive Cancer Network. (2018, March). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer. V 1.2018. Retrieved September 27, 2018 from www.nccn.org.
Ormeci, A., Emrence, Z., Baran, B., Soyer, O., Gokturk, S., Evirgen, S., et al. (2016). Can Helicobacter pylori be eradicated with high-dose proton pump inhibitor in extensive metabolizers with the CYP2C19 genotypic polymorphism? European Review for Medical and Pharmacological Sciences, 20, 1795-1797. (Level 5 evidence)
Prapitpaiboon, H., Mahachai, V., & Vilaichone, R. (2015). High efficacy of levofloxacin-dexlansoprazole-based quadruple therapy as a first line treatment for helicobacter pylori eradication in Thailand. Asian Pacific Journal Cancer of Cancer Prevention, 16 (10), 4353-4356. Abstract retrieved March 16, 2016 from PubMed database.
U. S. Food and Drug Administration. (2005, January). Center for Devices and Radiological Health. Medical devices. AmpliChip CYP450 Test for CYP2C19 510(k) Summary. Retrieved December 12, 2015 from https://www.accessdata.fda.gov.
ORIGINAL EFFECTIVE DATE: 11/12/2005
MOST RECENT REVIEW DATE: 12/13/2018
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