Coverage Policy Manual
Policy #: 2005003
Category: Laboratory
Initiated: January 2005
Last Review: July 2018
  Genetic Test: Cytochrome p450 Genotype Guided Treatment Strategy

Description:
The cytochrome p450 (CYP450) family is involved in the metabolism of a significant proportion of currently administered drugs, and genetic variants in cytochrome p450 are associated with altered metabolism of many drugs. Genetic testing for cytochrome p450 variants may assist in selecting and dosing drugs that are impacted by these genetic variants.
 
Background
Drug efficacy and toxicity vary substantially across individuals. Because drugs and doses are typically adjusted, if needed, by trial and error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.
 
Various factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Inherited (germline) DNA sequence variation (polymorphisms) in genes coding for drug metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the activity of those molecules and thus on the efficacy or toxicity of a drug.
 
Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA polymorphisms (genotyping) in genes related to the metabolic pathway (pharmacokinetics) or signal transduction pathway (pharmacodynamics) of the drug. Potentially, test results could be used to optimize drug choice and/or dose for more effective therapy, avoid serious adverse effects, and decrease medical costs.
 
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. Some CYP450 enzyme genes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzyme variants constitute one important group of drug-gene interactions influencing the variability of effect of some CYP450 metabolized drugs.
 
Individuals with 2 copies (alleles) of the most common (wild type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule are termed extensive metabolizers (EMs; normal). Poor metabolizers (PMs) lack active enzyme gene alleles, and intermediate metabolizers (IMs), who have one active and one inactive enzyme gene allele, may experience to a lesser degree some of the consequences of poor metabolizers. Ultrarapid metabolizers (UMs) are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.
 
Ultrarapid metabolizers administered an active drug may not reach therapeutic concentrations at usual recommended doses of active drugs, while PMs may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, UMs may suffer adverse effects and PMs may not respond.
 
However, it is very important to realize that many drugs are metabolized to varying degrees by more than one enzyme, either within or outside of the CYP450 superfamily. In addition, interaction between different metabolizing genes, interaction of genes and environment, and interactions among different non-genetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain inter-individual differences in metabolism and consequent efficacy or toxicity.
 
Genetically determined variability in drug response has been traditionally addressed using a trial and error approach to prescribing and dosing, along with therapeutic drug monitoring (TDM) for drugs with a very narrow therapeutic range and/or potential serious adverse effects outside that range. However, TDM is not available for all drugs of interest, and a cautious trial and error approach can lengthen the time to achieving an effective dose.
 
CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (e.g., in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.
 
The clinical utility of CYP450 genotyping, i.e., the likelihood that genotyping will significantly improve drug choice/dosing and consequent patient outcomes, is favored when the drug under consideration has a narrow therapeutic dose range (window), when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics, and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. Yet, the potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed the process of achieving a therapeutic dose and avoiding significant adverse events.
 
Regulatory Status   
CYP450 enzymes are now available. Some tests are offered as in-house laboratory-developed test services, which do not require U.S. Food and Drug Administration (FDA) approval but which must meet Clinical Laboratory Improvement Act (CLIA) quality standards for high-complexity testing.
  • The AmpliChip® (Roche Molecular Systems, Inc.) as cleared for marketing in January 2005. The AmpliChip® is a microarray consisting of many DNA sequences complementary to 2 CYP450 genes and applied in microscopic quantities at ordered locations on a solid surface (chip). The AmpliChip® tests the DNA from a patient’s white blood cells collected in a standard anticoagulated blood sample for 29 polymorphisms and mutations for the CYP2D6 gene and 2 polymorphisms for the CYP2C19 gene. FDA cleared the test “based on results of a study conducted by the manufacturers of hundreds of DNA samples as well as on a broad range of supporting peer-reviewed literature.” According to FDA labeling, “Information about CYP2D6 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment doses for therapeutics that are metabolized by the CYP2D6 product.”
  • The xTAG® CYP2D6 Kit (Luminex Molecular Diagnostics, Toronto) was cleared for marketing in August 2010 based on substantial equivalence to the Amplichip CYP450 test. It is designed to identify a panel of nucleotide variants within the polymorphic CYP2D6 gene on chromosome 22.
  • The INFINITI CYP2C19 Assay (AutoGenomics, Inc., Vista, CA) was cleared for marketing in October 2010 based on substantial equivalence to the Amplichip CYP450 test. It is designed to identify variants within the CYP2C19 gene (*2, *3, and *17)
  • Verigene CYP2C19 Nucleic Acid Test (Nanosphere, Inc., Northbrook, IL) , designed to identify variants within the CYP2C19 gene, was cleared for marketing in November 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.
  • The Spartan RX CYP2C19 Test System Spartan Bioscience, Redwood Shores, CA), designed to identify variants in the CYP2C19 gene (*2, *3, and *17 alleles), was cleared for marketing in August 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.
  • The xTAG® CYP2C19 Kit v3 (Luminex Molecular Diagnostics, Toronto), designed to identify variants in the CYP2C19 gene (*2, *3, and *17 alleles) was cleared for marketing in September 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.
 
Genelex offers YouScript®, a DNA panel which tests for genetic variants in CYP2D6, CYP2C9, CYP2C19 and VKORC1 combined with a software tool available to providers. The test and software is marketed to assist providers to help predict which medications will work best for the person tested. YouScript® has not received approval from the U.S. Food and Drug Administration. There were no clinical trials identified testing the clinical utility of YouScript®.
  
Pathway genomics offers a similar panel, Pain Management DNA Insight™.
 
Sky Toxicology offers SkyPGx a comprehensive pharmacogenetic panel which includes cytochrome genotyping. The test is marketed to identify a patient’s ability to metabolize a various prescription and non-prescription medications.
      
Coding
 
Effective in 2012, there is specific CPT coding for this testing:
 
81225: CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)
 
81226: CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
 
81227: CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6)
 
There are also Tier 2 CPT codes that include cytochrome P450 testing:
 
81401: Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) includes –
 
CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
 
CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
 
81402: Molecular pathology procedure, Level 3 (e.g., >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) includes –
 
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., congenital adrenal hyperplasia, 21-hydroxylase deficiency), common variants (e.g., IVS2-13G, P30L, I172N, exon 6 mutation cluster [I235N, V236E, M238K], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30- kb deletion variant)
 
81404: Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) includes –
 
CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (e.g., primary congenital glaucoma), full gene sequence
 
81405: Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) includes –
 
CYP11B1 (cytochrome P450, family 11, subfamily B, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
 
CYP17A1 (cytochrome P450, family 17, subfamily A, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
 
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., steroid 21-hydroxylase isoform, congenital adrenal hyperplasia), full gene sequence
 
Related Polices
Separate policies have been developed to address genetic testing of CYP450 enzymes for Tamoxifen and Warfarin Treatment:  
 
Policy 2009003-Genetic Test: Tamoxifen Treatment (CYP2D6).
 
Policy 2007015-Genetic Test: Warfarin Dose/Response
 
 

Policy/
Coverage:
EFFECTIVE JULY 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
 
        • With Gaucher disease being considered for treatment with eliglustat; OR
        • With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
        • Selection or dosing of clopidogrel
        • deciding whether to prescribe codeine for nursing mothers
        • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
        • dosing of immunosuppressant for organ transplantation
        • selection or dose of beta blockers (e.g., metoprolol)
        • dosing and management of antituberculosis medications
        • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (eg, the Genecept Assay). Genetic testing for mental health conditions is discussed in coverage policy 2013046.
 
 
EFFECTIVE PRIOR TO JULY 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
 
    • With Gaucher disease being considered for treatment with eliglustat; OR
    • With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • Selection or dosing of clopidogrel
    • selection or dosing of selective serotonin reuptake inhibitors (SSRI)
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE DECEMBER 2013 – FEBRUARY 2016
 
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the following applications:
 
    • Selection or dosing of clopidogrel
    • selection or dosing of selective serotonin reuptake inhibitors (SSRI)
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV [human immunodeficiency virus] infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
    • dosing and management of antituberculosis medications
    • dosing and management of pain medications
 
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  This includes, but is not limited to, CYP450 genotyping for the applications listed above.
 
Effective October 2013 to November 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:  
 
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norephinephrine reuptake inhibitors
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
 
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Note: CYP450 genotyping for Tamoxifen, Warfarin, Clopidogrel and drugs used to treat depression are handled in separate policies.
 
Effective October 2012 – August 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:
 
    • selection or dosing of antipsychotic drugs
    • deciding whether to prescribe codeine for nursing mothers
    • selection and dosing of selective norepinephrine reuptake inhibitors
    • selection and dosing of tricyclic antidepressants
    • dosing of efavirenz (common component of highly active antiretroviral therapy for HIV infection)
    • dosing of immunosuppressant for organ transplantation
    • selection or dose of beta blockers (e.g., metoprolol)
 
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Note: CYP450 genotyping for Tamoxifen, Warfarin, and clopidogrel are handled in separate policies.
 
Effective, May 2010
CYP450 phenotyping for CYP2C19 *2 and *3 alleles meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) in order to identify those who are poor metabolizers of the drug (patients with CYP2C19*2/2,*3/3, and *2/3 genotypes) and who are therefore likely to exhibit poor response to the drug.
 
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication does not meet member benefit certificate primary coverage criteria because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management.  
 
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication is considered investigational.   Investigational services are excluded in the member benefit certificate
 
Effective, January 2005 through April 2010
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is not covered because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management.  Therefore this testing does not meet Primary Coverage Criteria of effectiveness.
 
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational.   Investigational services are excluded in the member benefit certificate

Rationale:
The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes in compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.
 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
 
P450 genotype-guided TREATMENT strategy
 
Clinical Context and Therapy Purpose
The purpose of a P450 genotype-guided strategy is to tailor selection and dosing of drugs based on gene composition for drug metabolism. In theory, this should lead to early selection and optimal dosing of the most effective drugs, while minimizing treatment failures or toxicities.
 
The question addressed in this evidence review is: Does P450 genotype-guided strategy change patient management in a way that improves net health outcome?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant populations of interest are patients being considered for treatment with clopidogrel, eliglustat, tetrabenazine, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, antipsychotic drugs, codeine, efavirenz and other antiretroviral therapies for HIV infection, immunosuppressants for organ transplantation, β-blockers (eg, metoprolol), and antitubercular medications.
 
Interventions
Commercial tests for individual genes or gene panels are available and are listed in the Regulatory Status section. Only those panels that include CYP450 genes are listed in that section.
 
Comparators
The following practice is currently being used: standard clinical management without genetic testing.
 
Timing
Outcomes in the first 3 months are relevant because the interest is in whether P450 genotype-guided strategy reduces adverse events or avoids treatment failure.
 
Setting
Consultations about the choice of the drug generally occur in an outpatient setting, and a variety of specialists may be involved including primary care providers (HIV, β-blockers, tuberculosis and cough medications), cardiologists (clopidogrel), psychiatrists (antidepressants, antipsychotics), neurologists (Huntington disease), and endocrinologists (Gaucher disease).
 
Clopidogrel
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) is the standard of care for the prevention of subsequent atherothrombotic events such as stent thrombosis or recurrent acute coronary syndrome in patients who undergo a percutaneous intervention or who have an acute coronary syndrome.
 
Clopidogrel is a prodrug that is converted to its active form by several CYP450 enzymes (particularly CYP2C19). Individuals with genetic variants that inactivate the CYP2C19 enzyme are associated with lack of response to clopidogrel. There are several variants of CYP2C19 but the 2 most frequent variants associated with loss of function alleles are CYP2C19*2 and CYP2C19*3. It is hypothesized that such individuals may benefit from other drugs such as prasugrel or ticagrelor or a higher dose of clopidogrel. Approximately 30% of whites and blacks and 65% of Asians carry a nonfunctional CYP2C19 gene variant (Scott, 2013). While CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite, the variability in clinical response seen with clopidogrel may also result from other factors such as variable absorption, accelerated platelet turnover, reduced CYP3A metabolic activity, increased adenosine diphosphate exposure, or upregulation of P2Y12 pathways, drug-drug interactions, comorbidities (eg, diabetes, obesity), and medication adherence.
 
Multiple observational studies in patients undergoing percutaneous coronary intervention (PCI) have reported associations between the presence of loss of function alleles and lower levels of active clopidogrel metabolites, high platelet reactivity, and increased risk of adverse cardiovascular events. However, evidence of publication bias has been reported in these studies where smaller studies have reported larger benefits than larger studies which have reported no effect or smaller effect (Holmes, 2011). Wang et al reported post hoc analysis of the CHANCE trial conducted in China; it randomized patients with a transient ischemic attack or minor stroke to clopidogrel plus aspirin or aspirin alone. In a subgroup analysis of patients who did not have the loss of function alleles, clopidogrel plus aspirin vs aspirin alone was associated with statistical significant reduction in the risk of stroke (6.7% vs 12.4%; hazard ratio, 0.51; 95% confidence interval, 0.35 to 0.75) but not among those who carried loss of function alleles (9.4% vs 10.8%; hazard ratio, 0.93; 95% confidence interval, 0.69 to 1.26) (Wang, 2016). Results of this analysis have contributed to the formulation of the hypothesis of a differential effect of clopidogrel in patients with and without loss of function alleles.
 
Trials are important to validate such hypotheses. However, only a few trials of genotype-directed dosing or drug choice have been conducted. It is important to note that these trials use “high on-treatment platelet reactivity” as the outcome measure. Patients who exhibit “high on-treatment platelet reactivity” are referred to as being nonresponsive, hyporesponsive, or resistant to clopidogrel in the published literature.
 
Roberts et al reported on the results of RCT that allocated patients undergoing PCI for acute coronary syndrome or stable angina to genotype-guided management to select for treatment with prasugrel (carriers) or clopidogrel (noncarriers) or to standard treatment with clopidogrel (Roberts, 2012). Among those who received prasugrel and clopidogrel based on genotyping test, 0% and 10%, respectively, exhibited high on-treatment reactivity while 17% patients who received standard treatment with clopidogrel without any genotypes testing exhibited high on-treatment reactivity. This difference was not statistically significant. So et al reported on the results of an RCT that randomized ST-elevation myocardial infarction patients who were carriers of CYP2C19*2, ABCB1 TT, and CYP2C19*17 alleles to prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg/d for 6 days and subsequently 75 mg/d) (So, 2016). Results showed that (1) carriers did not respond to augmented clopidogrel as well as they did to prasugrel (24% patients with high platelet reactivity vs 0%) and (2) among noncarriers, physician-directed clopidogrel was effective for most patients (95% did not have high platelet reactivity).
 
The studies were, in general, well-designed and -conducted, the major limitation being the use of platelet activity, which is an intermediate outcome measure, and lack of reporting on health endpoints over a longer follow-up.
 
Platelet reactivity during treatment is an intermediate end point that has been shown to have a limited value in guiding therapeutic decisions based on results of the large ARTIC RCT (Collet, 2012; Montalsecot, 2014). Briefly, the ARCTIC trial randomized 2440 patients scheduled for coronary stenting to platelet-function monitoring or no monitoring. Platelet-function testing was performed in the monitored group both before and 14 to 30 days after PCI. Multiple therapeutic changes, including an additional loading dose of clopidogrel (at a dose ≥600 mg) or a loading dose of prasugrel (at a dose of 60 mg) before the procedure, followed by a daily maintenance dose of clopidogrel 150 mg or prasugrel 10 mg, were made according to a predefined protocol. There was no difference in the rate of the primary composite end point (death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization) at 1 year between the monitoring (34.6%) and no monitoring groups (31.1%). In the absence of results from well-performed randomized trials designed to evaluate this issue, performing routine genetic testing or ex vivo tests of platelet reactivity to predict CYP2C19 metabolic state and identify PMs has not been shown to improve health clinical outcomes. TAILOR-PCI (NCT01742117) is a large ongoing RCT that will randomize 5270 patients undergoing PCI to clopidogrel without prospective genotyping guidance or a prospective CYP2C19 genotype-based antiplatelet therapy approach (ticagrelor 90 mg bid in CYP2C19*2 or CYP2C19*3 reduced function allele patients, clopidogrel 75 mg once daily in non-CYP2C19*2 or -CYP2C19*3 patients). The trial is expected to be completed in March 2020.
 
Section Summary: Clopidogrel
Two RCTs have evaluated the role of genetic testing for CYP2C19 for selecting appropriate antiplatelet treatment and/or amplified dosing of clopidogrel using an intermediate outcome measure of platelet reactivity to predict CYP2C19 metabolic state. One RCT has shown there was no statistical difference in patients with “on-treatment high platelet reactivity” who received genotype-guided management or standard treatment with clopidogrel. The second RCT showed that carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, while physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap.
 
Selection and Dosing of Other Drugs
 
Antiretroviral Agents
Efavirenz is a widely used non-nucleoside reverse transcriptase inhibitor component of highly active antiretroviral therapy for patients with HIV infection. However, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with its use. Forty percent to 70% of patients have reported adverse central nervous system events. While most resolve in the first few weeks of treatment, about 6% of patients discontinue efavirenz due to adverse events (King, 2008). Efavirenz is primarily metabolized by the CYP2B6 enzyme, and inactivating variants such as CYP2B6*6 are associated with higher efavirenz exposure, although plasma levels appear not to correlate with adverse events. On the other hand, CYP2B6 PMs have markedly reduced adverse events while maintaining viral immunosuppression at substantially lower doses (Torno, 2008; Gatanaga, 2007). An increased early discontinuation rate with efavirenz has been reported in retrospective cohort studies evaluating multiple CYP450 variants including CYP2B6 (Wyen, 2011; Lubomirov, 2011). CYP2B6 G516T and T983C single nucleotide variants were reported by Ciccacci et al to be associated with susceptibility to Stevens-Johnson syndrome in a case-control study of 27 patients who received nevirapine-containing antiretroviral treatment (Ciccacci, 2013). The current evidence documenting the usefulness of CYP450 variant genotyping to prospectively guide antiretroviral medications and assess its impact on clinical outcomes is lacking.
 
Immunosuppressants for Therapy for Organ Transplantation
Tacrolimus is the mainstay immunosuppressant drug and multiple studies have shown that individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus, possibly delaying achievement of target blood concentrations compared with those who are CYP3A5 nonexpressers (PMs) in whom drug levels may be elevated and possibly result in nephrotoxicity. The current evidence demonstrating the impact of CYP3A5 genotyping to guide tacrolimus dosing and its impact on clinical outcomes is a limited RCT by Thervet et al (Thervet, 2010). This RCT compared the impact of CYP3A5 genotype-informed dosing with standard dosing strategies on tacrolimus drug levels. The trial was not powered to assess any clinical outcomes such as graft function or survival, which otherwise were similar between groups.
 
b-Blockers
Several reports have indicated that lipophilic b-blockers (eg, metoprolol), used in treating hypertension, may exhibit impaired elimination in patients with CYP2D6 variants (Bijl, 2009; Yuan, 2008). The current evidence documenting the usefulness of CYP2D6 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
 
Antitubercular Medications
A number of studies, summarized in a systematic review by Wang et al, have reported an association between CYP2E1 status and the risk of liver toxicity from antitubercular medications (Wang, 2016). The current evidence documenting the usefulness of CYP2E1 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
 
Section Summary: Selection and Dosing of Other Drugs
In general, most published CYP450 pharmacogenomic studies for highly active antiretroviral agents, b-blockers, and antitubercular medications are retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered, and hypothesis generating. Prospective intervention studies, including RCTs documenting clinical usefulness of CYP450 genotyping to improve existing clinical decision-making to guide dose or drug selection, which will then translate into improvement in patient outcomes, were not identified.
 
Summary of Evidence
 
Clopidogrel
For individuals with a need for antiplatelet therapy who are undergoing or being considered for clopidogrel therapy who receive a CYP2C19-guided treatment strategy, the evidence incudes 2 RCTs. Relevant outcomes are overall survival, medication use, and treatment-related morbidity. The 2 RCTs evaluated the impact of CYP2C19 genotyping using an intermediate outcome measure (platelet reactivity). One RCT showed no statistical difference between patients with on-treatment high platelet reactivity between genotype-guided management or standard treatment with clopidogrel. The second RCT showed carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, and physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Other Drugs
For individuals who are undergoing or being considered for treatment with highly active antiretroviral agents, immunosuppressant therapy for organ transplantation, b-blockers, or antitubercular medications who receive a CYP2C19-guided treatment strategy, the evidence includes retrospective studies. Relevant outcomes are medication use and treatment-related morbidity. In general, most published CYP450 pharmacogenomic studies for these drugs consist of retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered and hypothesis generating. Prospective intervention studies, including RCTs documenting the clinical usefulness of CYP450 genotyping to improve existing clinical decision making to guide dose or drug selection, which may then translate into improvement in patient outcomes, were not identified. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Supplemental Information
 
Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
 
In response to requests, input was received from 4 physician specialty societies and 4 academic medical centers while this policy was under review in 2012. Opinions on use of genotype testing of patients being considered for clopidogrel treatment were mixed, with 5 suggesting the test be considered investigational and 3 suggesting it be considered medically necessary.
 
Practice Guidelines and Position Statements
A consensus statement by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) on genetic testing for the selection and dosing of clopidogrel was published in 2010 (Holmes, 2010). The recommendations for practice included the following statements:
 
    1. “Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. Careful clinical judgment is required to assess the importance of the variability in response to clopidogrel for an individual patient and its associated risk to the patient…
    2. Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes in registry experiences and clinical trials.
    3. The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined....
    4. Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. The selection of the specific test, as well as the issue of reimbursement, is both important additional considerations.
    5. The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time…. 
    6. There are several possible therapeutic options for patients who experience an adverse event while taking clopidogrel in the absence of any concern about medication compliance.” 
 

CPT/HCPCS:
0031UCYP1A2 (cytochrome P450 family 1, subfamily A, member 2)(eg, drug metabolism) gene analysis, common variants (ie, *1F, *1K, *6, *7)
81225CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)
81226CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
81227CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
81230CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, *2, *22)
81231CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *7)
81401MOLECULAR PATHOLOGY PROCEDURE LEVEL 2
81402MOLECULAR PATHOLOGY PROCEDURE LEVEL 3
81404MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405MOLECULAR PATHOLOGY PROCEDURE LEVEL 6

References: Ramoz N, Boni C, Downing AM.(2009) . A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 2009; 34(9):2135-42.

Aleil B, Jacquemin L, De Poli F et al.(2008) Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: Results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv 2008; 1(6):631-8.

Almoguera B, Riveiro-Alvarez R, Lopez-Castroman J, et al.(2013) CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment. Pharmacogenet Genomics. Nov 2013; 23(11):627-630. PMID 24026091

Angiolillo DJ, Shoemaker SB, Desai B et al.(2007) Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115(6):708-16.

Batty JA, Hall AS, White HL, et al.(2014) An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy. Clin Pharmacol Ther. Mar 2014;95(3):321-330. PMID 24193112

Baudhuin LM, Miller WL, Train L et al.(2010) Relation of ADRB1, CYP2D6, and UGT1A1 polymorphisms with dose of, and response to, carvedilol or metoprolol therapy in patients with chronic heart failure. Am J Cardiol 2010; 106(3):402-8.

Bennett LL, Turcotte K.(2015) Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Des Devel Ther. 2015;9:4639-4647. PMID 26345314

Bertilsson L.(2007) Metabolism of antidepressant and neuroleptic drugs by cytochrome p450s: clinical and interethnic aspects. Clin Pharmacol Ther 2007; 82(5):606-9.

Bienvenu E, Swart M, Dandara C, et al.(2014) The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients. Antiviral Res. Feb 2014;102:44-53. PMID 24316028

Bijl MJ, Visser LE, van Schaik RH et al.(2008) Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta blocker users. Clin Pharmacol Ther 2008; 85(1):45-50.

Bishop JR, Ellingrod VL.(2004) Neuropsychiatric pharmacogenetics: moving toward a comprehensive understanding of predicting risks and response. Pharmacogenomics 2004; 5(5):463-77.

Bondy B, Spellmann I.(2007) Pharmacogenetics of antipsychotics: useful for the clinician? Curr Opin Psychiatry 2007; 20(2):126-30.

Boughton O, Borgulya G, Cecconi M, et al.(2013) A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients. Br J Clin Pharmacol. Sep 2013;76(3):425-431. PMID 23305195

Cabrera SE, Santos D, Valverde MP et al.(2009) Influence of the cytochrome P450 2B6 genotype on population pharmacokinetics of efavirenz in human immunodeficiency virus patients. Antimicrob Agents Chemother 2009; 53(7):2791-8.

Campo G, Fileti L, Valgimigli M et al.(2010) Poor response to clopidogrel: current and future options for its management. J Thromb Thrombolysis 2010 [E-pub ahead of print].

Campo G, Valgimigli M, Gemmati D et al.(2007) Poor responsiveness to clopidogrel drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine study. . J Am Coll Cardiol 2007; 50(12):1132-5.

Chang M, Tybring G, Dahl ML, et al.(2014) Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis. Clin Pharmacokinet. Sep 2014;53(9):801-811. PMID 25154506

Ciccacci C, Di Fusco D, Marazzi MC, et al.(2013) Association between CYP2B6 polymorphisms and Nevirapine-induced SJS/TEN: a pharmacogenetics study. Eur J Clin Pharmacol. Nov 2013;69(11):1909-1916. PMID 23774940

Collet JP, Cuisset T, Range G, et al.(2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. Nov 29 2012;367(22):2100-2109. PMID 23121439

Collet JP, Hulot JS, Pena A et al.(2009) Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. . Lancet 2009; 373(9660):309-17.

Crescenti A, Mas S, Gasso P et al.(2008) Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol 2008; 35(7):807-11.

Cuisset T, Frere C, Quilici J et al.(2008) Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel non-responders: a prospective, randomized study. JACC Cardiovas Interv 2008; 1(6):649-53.

de Leon J, Susce MT, Pan RM et al.(2005) The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 2005; 66:15-27.

de Leon J.(2007) The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultrarapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 or CYP2C19. J Clin Psychopharmacol 2007; 27(3):241-5.

de Leon J.(2007) The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultrarapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 or CYP2C19. J Clin Psychopharmacol 2007; 27(3):241-5.

de Vos A, van der Weide J, Loovers HM.(2011) Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J 2011; 11(5):359-67.

Desai NR, Canestaro WJ, Kyrychenko P, et al.(2013) Impact of CYP2C19 genetic testing on provider prescribing patterns for antiplatelet therapy after acute coronary syndromes and percutaneous coronary intervention. Circ Cardiovasc Qual Outcomes. Nov 2013;6(6):694-699. PMID 24192573

Dorado P, Berecz R, Penas-Lledo EM et al.(2006) Clinical implications of CYP2D6 genetic polymorphism during treatment with antipsychotic drugs. Curr Drug Targets 2006; 7(12):1671-80.

Eli Lilly and Co.(2009) Strattera™ (atomoxetine HCl) product information Available online at: http://pi.lilly.com/us/strattera-pi.pdf. Last accessed February 2009.

FDA Center for Drug Evaluation and Research. Summary Review for Regulatory Action: Cerdelga/eliglustat tartrate. 2014; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205494Orig1s000SumR.pdf. Accessed October 29, 2015.

FDA.(2015) Highlights of Prescribing Information: Xenazine (tetrabenazine). 2015; http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf. Accessed November 3, 2015.

Fleeman N, Dundar Y, Dickson R et al.(2011) Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses. Pharmacogenomics J 2011; 11(1):1-14.

Fleeman N, McLeod C, Bagust A et al.(2010) The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation. Health Technol Assess 2010; 14(3):1-157.

Food and Drug Administration.(2013) Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy Drug Safety Communications 2013; http://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf. Accessed September, 2014

Frere C, Cuisset T, Morange PE et al.(2008) Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101(8):1088-93.

Gage BF, Eby C, Milligan PE, et al.(2004) Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91(1):87-94.

Gatanaga H, Hayashida T, Tsuchiya K et al.(2007) Successful efavirenz dose reduction in HIV type 1- infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis 2007; 45(9):1230-7.

Genzyme.(2014) Highlights of Prescribing Information: Cerdelga (eliglustat). http://www.cerdelga.com/pdf/cerdelga_prescribing_information.pdf. Accessed May 24, 2018.

Gex-Fabry M, Eap CB, Oneda B et al.(2008) CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit 2008; 30(4):474-82.

Gladding P, Webster M, Ormiston J et al.(2008) Antiplatelet drug nonresponsiveness. Am Heart J 2008; 155(4):591-9.

Gladding P, Webster M, Zeng I et al.(2008) The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1(6):612-9.

Gladding P, Webster M, Zeng I et al.(2008) The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1(6):620-7.

Gurbel PA, Antonino MJ, Bliden KP et al.(2008) Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19(8):595-604.

Hesselink DA, van Gelder T, van Schaik RH et al.(2004) Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes. Clin Pharmacol Ther 2004; 76:545-56.

Hillman MA, Wilke RA, Caldwell MD, et al.(2004) Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype. Pharmacogenetics 2004; 14:539-47.

Hodgson K, Tansey K, Dernovsek MZ, et al.(2014) Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. Feb 2014;28(2):133-141. PMID 24257813

Holmes DR, Jr., Dehmer GJ, Kaul S, et al.(2010) ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. Jul 20 2010;56(4):321-341. PMID 20633831

Holmes MV, Perel P, Shah T, et al.(2011) CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. Dec 28 2011;306(24):2704-2714. PMID 22203539

Hung CC, Lin CJ, Chen CC et al.(2004) Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther Drug Monit 2004; 26:534-40.

Huntington Study Group.(2006) Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Feb 14 2006;66(3):366-372. PMID 16476934

Jin Y, Desta Z, Stearns V et al.(2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005; 97:30-9.

Jornil J, Jensen KG, Larsen F et al.(2011) Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator. Eur J Pharm Sci 2011; 44(3):265-72.

Jovanovic N, Bozina N, Lovric M et al.(2010) The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naive patients with first-episode schizophrenia treated with risperidone. Eur J Clin Pharmacol 2010; 66(11):1109-17.

King J, Aberg JA.(2008) Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS 2008; 22(14):1709-17.

Kirchheiner J, Brockmoller J.(2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol The 2005r; 77:1-16.

Kirchheiner J, Brosen K, Dahl ML, et al.(2001) CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psych Scand 2001; 104(3):173-92.

Kirchheiner J, Heesch C, Bauer S, et al.(2004) Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2004; 76:30212.

Kirchheiner J, Nickchen K, Bauer M, et al.(2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9(5):442-73.

Kirchheiner J, Nickchen K, Bauer M, et al.(2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9:442-73.

Koren G, Cairns J, Chitayat D et al.(2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368(9536):704.

Lee KY, Lin SW, Sun HY, et al.(2014) Therapeutic drug monitoring and pharmacogenetic study of HIVinfected ethnic chinese receiving efavirenz-containing antiretroviral therapy with or without rifampicin-based anti-tuberculous therapy. PLoS One. 2014;9(2):e88497. PMID 24551111

Lehmann D, Nelsen J, Ramanath V, et al.(2004) Lack of attenuation in the antitumor effect of tamoxifen by chronic CYP isoform inhibition. J Clin Pharmacol 2004; 44(8):861-5.

Lobello KW, Preskorn SH, Guico-Pabia CJ et al.(2010) Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder. J Clin Psychiatry 2010; 71(11):1482-7.

Lubomirov R, Colombo S, di Iulio J et al.(2011) Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis 2011; 203(2):246-57.

Macaluso M, Preskorn SH.(2011) CYP 2D6 PM status and antidepressant response to nortriptyline and venlafaxine: is it more than just drug metabolism? J Clin Psychopharmacol 2011; 31(2):143-5.

MacPhee IA, Holt DW.(2008) A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation 2008; 85(2):163-5.

Madadi P, Ross CJ, Hayden MR et al.(2009) Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther 2009; 85(1):31-5.

Maier W, Zobel A.(2008) . Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics. Eur Arch Psychiatry Clin Neurosci 2008; 258(Suppl 1):12-20.

Mao L, Jian C, Changzhi L, et al.(2013) Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. Oct 2013;106(10):517-527. PMID 24080325

Mega JL, Close SL, Wiviott SD et al.(2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360(4):354-62.

Michelson D, Read HA, Ruff DD et al.(2007) CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2007; 46(2):242-51.

Michelson D, Read HA, Ruff DD et al.(2007) CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 2007; 46(2):242-51.

Montalescot G, Range G, Silvain J, et al.(2014) High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study. Circulation. May 27 2014;129(21):2136-2143. PMID 24718568

Mourad M, Wallemacq P, De Meyer M et al.(2008) Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome. Transplantation 2008; 85(7 Suppl):S19-24.

Murray M, Petrovic N.(2006) Cytochromes P450: decision-making tools for personalized therapeutics. Curr Opin Mol Ther 2006; 8(6):480-6.

Murray M.(2006) Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents. J Pharm Pharmacol 2006; 58(7):871-85.

Nyakutira C, Roshammar D, Chigutsa E et al.(2008) High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol 2008; 64(4):357-65.

Panagiotidis G, Arthur HW, Lindh JD et al.(2007) Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. . Ther Drug Monit 2007; 29(4):417-22.

Passey C, Birnbaum AK, Brundage RC, et al.(2011) Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. Dec 2011;72(6):948-957. PMID 21671989

Porto I, Giubilato S, De Maria GL et al.(2009) Platelet P2Y212 receptor inhibition by thienopyridines: status and future. Expert Opin Investig Drugs 2009; 18(9):1317-32.

Ramoz N, Boni C, Downing AM et al.(2009) . A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 2009; 34(9):2135-42.

Roberts JD, Wells GA, Le May MR, et al.(2012) Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. May 5 2012;379(9827):1705-1711. PMID 22464343

Scott SA, Sangkuhl K, Stein CM, et al.(2013) Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. Sep 2013;94(3):317-323. PMID 23698643

Serretti A, Calati R, Massat I et al.(2009) Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes are not associated with response and remission in a sample of depressive patients. Int Clin Psychopharmacol 2009; 24(5):250-6.

Shuldiner AR, O’Connell JR, Bliden KP et al.(2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302(8):849-57.

Sibbing D, Koch W, Gebhard D et al.(2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121(4):512-8.

Sibbing D, Stegherr J, Latz W et al.(2009) Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30(9):916-22.

Simon T, Verstuyft C, Mary-Krause M et al.(2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360(4):363-75.

Skinner MH, Kuan HY, Pan A et al.(2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003; 73(3):170-7.

Smoller JW.(2006) Incorporating pharmacogenetics into clinical practice: reality of a new tool in psychiatry. Practical issues related to medication selection. CNS Spectr 2006; 11(3 Suppl 3):5-7.

So DY, Wells GA, McPherson R, et al.(2016) A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study. Pharmacogenomics J. Feb 2016;16(1):71-78. PMID 25850030

TEC Special Report: Genotyping for Cytochrome P450 Polymorphisms to Determine DrugMetabolizer Status. 2004 Blue Cross Blue Shield Association Technology Evaluation Center Assessment Program Volume 19, No. 9.

ter Laak MA, Temmink AH, Koeken A et al.(2010) Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity. Pediatr Neurol 2010; 43(3):159-62.

Thervet E, Loriot MA, Barbier S, et al.(2010) Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. Jun 2010;87(6):721-726. PMID 20393454

Throckmorton, D.(2017) FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm. Accessed May 24, 2018.

Torno MS, Witt MD, Saitoh A et al.(2008) Successful use of reduced-dose efavirenz in a patient with human immunodeficiency virus infection: case report and review of the literature. Pharmacotherapy 2008; 28(6):782-7.

Trzepacz PT, Williams DW, Feldman PD et al.(2008) CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol 2008; 18(2):79-86.

Trzepacz PT, Williams DW, Feldman PD et al.(2008) CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol 2008; 18(2):79-86.

Tsai MH, Lin KM, Hsiao MC, et al.(2010) Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics. Apr 2010; 11(4):537-546. PMID 20350136

Tsuchiya N, Satoh S, Tada H, et al.(2004) Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004; 78:182-87.

U.S. Food and Drug Administration. Information for Healthcare Professionals: Use of Codeine Products in Nursing Mothers. Available online at http://www.fda.gov/cder/drug/InfoSheets/HCP/codeineHCP.htm. Last accessed February 2009.

Valgimigli M, Campo G, de Cesare N et al.(2009) Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention. Circulation 2009; 119(25):3215-22.

Vandel P, Talon JM, Haffen E et al.(2007) Pharmacogenetics and drug therapy in psychiatry--the role of the CYP2D6 polymorphism. Curr Pharm Des 2007; 13(2):241-50.

Ververs FF, Voorbij HA, Zwarts P et al.(2009) Effect of cytochrome P450 2D6 genotype on maternal paroxetine plasma concentrations during pregnancy. Clin Pharmacokinet 2009; 48(1):677-83.

Waade RB, Hermann M, Moe HL, et al.(2014) Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups. Eur J Clin Pharmacol. Aug 2014; 70(8):933-940. PMID 24858822013

Wadelius M, Sorlin K, Wallerman O, et al.(2004) Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 2004; 4(1):40-8.

Wang FJ, Wang Y, Niu T, et al.(2016) Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies. J Clin Pharm Ther. Jun 2016;41(3):334-340. PMID 27062377

Wang Y, Zhao X, Lin J, et al.(2016) Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA. Jul 5 2016;316(1):70-78. PMID 27348249

Wernicke JF, Kratochvil CJ.(2002) Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002; 63 Suppl 12:50-5.

Wernicke JF, Kratochvil CJ.(2002) Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002; 63(suppl 12):50-5.

Wiviott SD, Braunwald E, McCabe CH et al.(2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357(20):2001-15.

Wojtczak A, Wojtczak M, Skretkowicz J.(2014) The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease. Pharmacol Rep. Jun 2014;66(3):511-514. PMID 24905532

Wyen C, Hendra H, Siccardi M et al.(2011) Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J Antimicrob Chemother 2011; 66(9):2092-8.

Yuan H, Huang Z, Yang G et al.(2008) Effects of polymorphism of the beta(1) adrenoreceptor and CYP2D6 on the therapeutic effects of metoprolol. J Int Med Res 2008; 36(6):1354-62.

Zhao W, Elie V, Roussey G et al.(2009) Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther 2009; 86(6):609-18.

Zineh I, Beitelshees AL, Gaedigk A, et al.(2004) Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 2004; 76:536-44.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.