Pharmacogenetics Testing AHS – M2021

Description of Procedure or Service

Definitions

Pharmacogenetics is defined as the study of variability in drug response due to heredity (Nebert, 1999).

Cytochrome P450 enzymes are a class of enzymes essential in the synthesis and breakdown metabolism of various molecules and chemicals. Found primarily in the liver, these enzymes are also essential for the metabolism of many medications. Cytochrome P450 are essential for the production of many molecules including steroid hormones and certain fats, including cholesterol, fatty acids, and bile acids. Additional cytochrome P450 are involved in the metabolism of drugs, carcinogens, and internal substances, such as toxins formed within cells. Mutations in cytochrome P450 genes can result in the inability to properly metabolize medications and other substances, leading to increased possibility of toxic substance levels in the body. There are approximately 57 CYP genes in humans (Bains, 2013; National Institutes of Health, 2017).

Thiopurine methyltransferase (TPMT) is an enzyme that methylates azathioprine, mercaptopurine and thioguanine into active thioguanine nucleotide metabolites. The azathioprine and mercaptopurine is used for treatment of nonmalignant immunologic disorders, mercaptopurine is used for treatment of lymphoid malignancies and thioguanine is used for treatment of myeloid leukemias (Relling et al., 2011).

Dihydropyrimidine dehydrogenase (DPYD) gene is encoding for dihydropyrimidine dehydrogenase (DPD) enzyme responsible for fluoropyrimidine catabolism. It is a rate-limiting enzyme. The fluoropyrimidines (5-fluorouracil and capecitabine) are drugs used in the treatment of solid tumors such as colorectal, breast and aerodigestive tract tumors (Amstutz et al., 2018). Human Leukocyte antigens (HLAs) Human Leukocyte antigens is a group of genes that encode a variety of cell surface proteins such as antigen-presenting molecules and other proteins. HLAs are also known as major histocompatibility complex.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for pharmacogenetics testing when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Pharmacogenetics Testing is covered

1. Testing for the CYP2D6 genotype once per lifetime (please see policy guideline below)* is considered medically necessary for individuals being considered for therapy with any of the medication listed below, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing.
   • Eliglustat
   • Tetrabenazine (for doses over 50 mg)
2. Testing for the TPMT genotype once per lifetime (please see policy guideline below)* is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing.
   • Azathioprine
   • Mercaptopurine
   • Thioguanine
3. Testing for the following Human Leukocyte Antigens (HLAs) genotypes once per lifetime is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   • HLA-B*57:01 before treatment with Abacavir
   • HLA-B*15:02 for treatment with Carbamazepine limited to patients of Asian descent
4. Testing for the following genotypes once per lifetime is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing.
   • CFTR for treatment with Ivacaftor
   • G6PD for treatment with Rasburicase, Primaquine, Chloroquine and Dapsone

When Pharmacogenetics Testing is not covered

1. Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary.
2. The following pharmacogenetics testing is considered is considered investigational
   1. Genotyping for any medication therapy more than once per lifetime (please see policy guideline below)*
   2. Testing for the specific genotype for individuals on medications not listed as meeting coverage criteria for testing.
   3. Testing for all other genotypes including, but not limited to, use of other medication therapy not listed as meeting coverage criteria.
   4. Genotyping the general population.
3. Genetic testing to aid in therapy selection and/or dosing medication and/or monitoring either as individual single nucleotide polymorphism (SNP) testing or as a panel of SNPs is considered investigational for all indications. The list of SNPs includes, but is not limited to the following:
   • 5HT2C (serotonin receptor)
   • 5HT2A (serotonin receptor)
   • SLC6A4 (serotonin transporter)
   • DRD1 (dopamine receptor)
   • DRD2 (dopamine receptor)
   • DRD4 (dopamine receptor)
   • DAT1 or SLC6A3 (dopamine transporter)
   • DBH (dopamine beta-hydroxylase)
   • COMT (catechol-O-methyl-transferase)
   • MTHFR (methylenetetrahydrofolate reductase)
   • γ-Aminobutyric acid (GABA) A receptor
   • OPRM1 (µ-opioid receptor)
   • OPRK1 (κ-opioid receptor)
   • UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
   • Cytochrome P450 genes: CYP3A4, CYP2B6, CYP1A2

*Policy Guideline: Genotypic once per lifetime

Any gene should be tested once per lifetime regardless the indication (except would be for HLA where a specific variant is tested for the medication). For example, if CYP2C19 was tested for therapy with citalopram, additional testing for CYP2C19 for treatment with clopidogrel is not needed and is considered investigational. 

Policy Guidelines

Background

Genetic variations play a role in an individual’s response to medications. Drug metabolism and responses are affected by many factors including age, sex, interactions with other drugs, and disease states with genetic variations offering only a partial explanation of an individual's response (Stamer & Stuber, 2007). However, inherited differences in the metabolism and disposition of drugs and genetic polymorphisms in the targets of drug therapy can have a significant influence on the efficacy and toxicity of medications (Kapur, Lala, & Shaw, 2014) potentially even more so than clinical variables such as age and organ function (Ting & Schug, 2016). Genetic variation can influence pharmacodynamics factors, through variations affecting drug target receptors and downstream signal transduction, or pharmacokinetic factors, affecting drug metabolism and/or elimination, ultimately altering the relationship between drug dose and steady state serum drug concentrations. Development of tolerance, which may occur through both dynamic and kinetic mechanisms, can also play a significant role in this response variation (Nielsen et al., 2015).

The Cytochrome P450 (CYP 450) system is a group of enzymes responsible for the metabolism of many endogenous and exogenous substances, including many pharmaceutical agents. They may serve to “activate” an inactive form of a drug, and they may serve a role in the inactivation and/or clearance of a drug from circulation. The CYP 450 enzymes are responsible for the clearance of over half of all drugs, and their activity can be affected by diet, age, and other medications. The genes encoding for the CYP 450 enzymes are highly variable, with multiple alleles that confer various levels of metabolic activity for specific substrates. Nomenclature for CYP 450 enzymes reflects the gene family (which is a number), the subfamily (which is a letter), the isoenzyme (which is a number), and the allele (which is noted by a * preceding a number). In some cases, alleles can be highly correlated with ethnic background.

The most common alleles are sometimes referred to as “wild type,” while other alleles are said to confer lower or higher activity than normal. Individuals with these allelic types are sometimes referred to as “poor metabolizers” or “ultra-rapid metabolizers,” although standard nomenclature relative to the activity of variant alleles is lacking.

Due to the variations in enzyme activity conferred by allelic differences, some CYP 450 alleles are associated with increased risk for certain conditions or adverse outcomes with certain drugs. Knowledge of the allele type may assist in the selection of a drug, or in drug dosing. Three CYP 450 enzymes are most often considered with regard to clinical use for drug selection and/or dosing. CYP2D6, CYP2C9m and CYP2C19 have each been associated with the metabolism of several therapeutic drugs, and each of them exists in a variety of allelic forms, many of which confer differences in metabolic function.

For these CYP 450 enzymes, it is thought that “poor metabolizers” could have less efficient elimination of a drug, and therefore may be at risk for side effects due to drug accumulation. For drugs that require activation by a particular CYP 450 enzyme, lower activity may yield less biologically active drug, which could result in lower drug effectiveness. Individuals defined as “ultra-rapid metabolizers” may clear the drug more quickly than normal, and therefore may require higher doses to yield the desired therapeutic effect. Likewise, for drugs that require activation, these individuals may produce higher levels of active drug, which could cause side effects.

CYP2C9

Warfarin (brand name Coumadin) is widely used as an anticoagulant in the treatment and prevention of thrombotic disorders. CYP2C9 participates in warfarin metabolism, and several CYP2C9 alleles have reduced activity, resulting in higher circulating drug concentration. CYP2C9*2 and CYP2C9*3 are the most common variants with reduced activity. Individuals with these alleles may require lower doses of warfarin than those who metabolize the drug normally. Variations in a second gene, VKORC1, also can impact warfarin’s effectiveness. This gene codes for the enzyme that is the target for warfarin, and individuals who have the -1639G>A polymorphism have higher sensitivity to warfarin, and will need lower doses.

CYP2C19

Clopidogrel (brand name, Plavix), which is used to inhibit platelet aggregation, is given as a prodrug that is metabolized to its active form by CYP2C19. Alleles CYP2C19*2 and CYP2C19*3 are associated with reduced metabolism of clopidogrel. Individuals with the “poor metabolizer” alleles may not benefit from clopidogrel treatment at standard doses.

CYP2D6

Tetrabenazine (brand name Xenazine) is used in the treatment of chorea associated with Huntington’s disease. This drug is metabolized for clearance primarily by CYP2D6. Poor metabolizers are considered to be those individuals who have two copies of non- functional alleles: *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *19, *20, *21, *38, *40, *42. Poor metabolizers will have significantly higher levels of the drug’s primary active metabolites than patients who are extensive metabolizers, which can cause increased side effects. Tamoxifen, a drug commonly used for treatment and prevention of recurrence of estrogen receptor positive breast cancer, is metabolized by CYP2D6. Several studies have examined recurrence rates and overall survival in individuals with different CYP2D6 genotypes, but results have not been consistent.

Codeine, which is commonly used to treat mild to moderate pain, is metabolized to morphine, a much more powerful opioid, by CYP2D6. Differences in CYP2D6 alleles can result in different amounts of morphine produced. Individuals with variants that have little to no CYP2D6 activity will not get pain relief from codeine. Conversely, those with variants that have higher than normal activity are at risk for negative side effects of morphine, including CNS depression. Those most vulnerable for these side effects are ultra-rapid metabolizer children who are prescribed codeine and breast-feeding infants of ultra-rapid metabolizer mothers who are prescribed codeine.

TPMT

Thiopurine methyltransferase (TPMT) is an enzyme that methylates thiopurines into active thioguanine nucleotides. The TPMT gene is inherited as a monogenic co-dominant trait and there are ethnic differences in the frequencies of low-activity variant alleles. Individuals who inherit two inactive TPMT alleles will develop severe myelosuppression. Individuals that inherit only one inactive TPMT allele will develop moderate to severe myelosuppression and those individuals who are normal or inherit both active TPMT alleles will have lower risk of myelosuppression. Therefore, genotyping for TPMT is critical before starting therapy with thiopurine drugs (Relling et al., 2011).

DPYD

Dihydropyrimidine dehydrogenase (DPYD) gene is encoding for rate-limiting enzyme dihydropyrimidine dehydrogenase involved in catabolism of fluoropyrimidines drugs used in treatment of solid tumors. Decreased DPD activity increases the risk for sever or even fatal drug toxicity when patients are being treated with fluoropyrimidine drugs. There are numerous genetic variants in DPYD gene identified that alter the protein sequence or mRNA splicing. However, some of these variants have no effect on DPD enzyme activity. The most studied causal variant of DPYD haplotype (HapB3) spans intron 5 to exon 11 and affects protein function. The most common in Europeans HapB3 with c.1129–5923C>G DPYD variant demonstrates decreased function with carrier frequency of 4.7%, followed by c.190511G>A (carrier frequency: 1.6%) and c.2846A>T (carrier frequency: 0.7%). There are approximately 7% of Europeans that carry at least one decreased function DPYD variant. In people with African ancestry, the most common variant c.557A>G (rs115232898, p.Y186C) is relatively common (3–5% carrier frequency). Other DPYD decreased function variants are rare. Therefore, most of genetic tests available are focusing on identification of most common variants with well-established risk: (c.190511G>A, c.1679T>G, c.2846A>T, c.1129– 5923C>G) (Amstutz et al., 2018).

HLAs

Human Leukocyte antigens (HLAs) region is divided into 3 regions such as class I, class II and class III. Each class has many gene loci, expressed genes and pseudogenes. The class I encodes HLA-A, HLA-B, HLA-C and other antigens. The class II encodes HLA-DP, DQ and DR. The class III region is located between class I and class II and does not encode any HLAs, but other immune response proteins (Viatte, 2017).

Applicable Federal Regulations

Diagnostic genotyping tests for certain 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.) is the FDA-cleared test for CYP450 genotyping. 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. CYP2D6 metabolizes approximately 25 percent of all clinically used medications (e.g., dextromethorphan, beta-blockers, antiarrhythmics, antidepressants, and morphine derivatives), including many of the most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton-pump inhibitors, diazepam, propranolol, imipramine, and amitriptyline. 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 AmpliChip was the only FDA approved test in 2005. Currently, there are over 10 FDAapproved tests for the drug metabolizing enzymes that are nucleic acid-based tests including xTAG CYP2D6 Kit v3 (Luminex Molecular Diagnostics, Inc), Spartan RX CYP2C19 Test System (Spartan Bioscience, Inc), Verigen CYP2C19 Nucleic Acid Test (Nanosphere, Inc), INFINITI CYP2C19 Assay (AutoGenomics, Inc), Invader UGT1A1, eSensor Warfarin Sensitivity Saliva Test (GenMark Diagnostics), eQ-PCR LC Warfarin Genotyping kit (TrimGen Corporation), eSensor Warfarin Sensitivity Test and XT-8 Instrument (Osmetech Molecular Diagnostics), Gentris Rapid Genotyping Assay-CYP2C9&VKORCI (ParagonDx, LLC), INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin (AutoGenomics, Inc) and Verigene Warfarin Metabolism Nucleic Acid Test and Verigene System (Nanosphere, Inc) (accessed on 02/21/2018 from https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm330 711.htm).

Guidelines and Recommendations

United States Food and Drug Administration (US FDA)

Per the US FDA (2018), “Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose.” The Office of Clinical Pharmacology within FDA includes The Genomics and Targeted Therapy Group responsible for applying pharmacogenomics and other biomarkers in drug development and clinical practice. The FDA scientists review current pharmacogenomic information and ensure that pharmacogenomic strategies are utilized appropriately in all phases of drug development.

In 2016, US FDA drug labels included pharmacogenetic information for about 10% of all drug labels approved by FDA (Dean, 2016). Current list of pharmacogenomic biomarkers in drug labeling by FDA contains a total of 92 medications that have cytochrome P450 enzymes related to metabolism dosage recommendations or warnings. These medications are involved in different therapeutic areas and the list includes the following medications (accessed on 2/13/2018 from https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm):

CYP1A2: Rucaparib

CYP2B6: Efavirenz

CYP2C19 contains 22 different medications: Clopidogrel, Prasugrel, Ticagrelor, Lansoprazole, Omeprazole, Esomeprazole, Rabeprazole, Pantoprazole, Dexlansoprazole, Flibanserin, Drospirenone and Ethinyl Estradiol, Voriconazole, Lacosamide, Brivaracetam, Clobazam, Phenytoin, Diazepam, Citalopram, Escitalopram, Doxepin, Formoterol, Carisoprodol

CYP2C9 contains 9 different medications: Prasugrel, Dronabinol, Flibanserin, Warfarin, Phenytoin, Celecoxib, Piroxicam, Flurbiprofen, Lesinurad

CYP2D6 contains 57 different medications: Codeine, Tramadol, Carvedilol, Metoprolol, Nebivolol, Propafenone, Propranolol, Quinidine, Cevimeline, Ondansetron, Palonosetron, Flibanserin, Eliglustat, Quinine Sulfate, Deutetrabenazine, Dextromethorphan and Quinidine, Galantamine, Tetrabenazine, Valbenazine, Rucaparib, Amitriptyline, Aripiprazole, Aripiprazole Lauroxil, Atomoxetine, Brexpiprazole, Cariprazine, Citalopram, Clomipramine, Clozapine, Desipramine, Desvenlafaxine, Doxepin, Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Iloperidone, Imipramine, Modafinil, Nefazodone, Nortriptyline, Paroxetine, Perphenazine, Pimozide, Protriptyline, Risperidone, Thioridazine, Trimipramine, Venlafaxine, Vortioxetine, Arformoterol, Formoterol, Umeclidinium, Darifenacin, Fesoterodine, Mirabegron, Tolterodine

CYP3A5: Prasugrel

U. S. Food and Drug Administration (FDA) package inserts

The FDA package insert for Plavix (clopidogrel) carries the following “Black Box” warning: “Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.”

The FDA package insert for Xenazine (tetrabenazine) indicates, “Patients who require doses of Xenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of XENAZINE should then be individualized accordingly to their status as PMs or EMs. The maximum daily dose in PMs is 50 mg with a maximum single dose of 25 mg. The maximum daily dose in EMs and intermediate metabolizers (IMs) 100 mg with a maximum single dose of 37.5 mg.”

The Coumadin (warfarin) package insert notes that “the dose of Coumadin must be individualized by monitoring the PT/INR. The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose.” Although dosage suggestions based on CYP2C9 and VKORC1 genotypes are provided in the package insert, the requirement for genetic testing is not included.

The eligibility and dosing of Eliglustat is dependent on cytochrome P450 CYP2D6 genotype as eliglustat is extensively metabolized by CYP2D6 and the CYP2D6 metabolizer phenotype was the most significant determinant of eliglustat blood concentrations (Balwani et al, 2016; Bennett and Turcotte, 2015; Scott, 2015). Patients are classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) or ultra-rapid metabolizers.

Practice Guidelines and Position Statements

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline

CPIC guidelines provide guidance to physicians on how to use genetic testing to help them to optimize drug therapy. The guidelines and projects were endorsed by several professional societies including The Association for Molecular Pathology (AMP), The American Society for Clinical Pharmacology and Therapeutics (ASCPT) and The American Society of Health-System Pharmacists (ASHP) (www.cpicpgx.org, 2018).

In their guidelines, CPIC provides specific therapeutic recommendations for drugs metabolized by Cytochrome P450 enzymes and other important metabolic enzymes.