Description
Pharmacogenetics aims to study the influence of genetic variation on drug response and drug toxicity, which allows physicians to select a more targeted therapeutic strategy to suit each patient’s genetic profile. Genetic variations in human proteins, such as cytochrome P450 enzymes, Thiopurine methyltransferase (TPMT), Dihydropyrimidine dehydrogenase (DPD), and cell surface proteins, highlights the clinical importance of pharmacogenetic testing.

Cytochrome (CYP) 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. CYP P450 enzymes, approximately 58 CYP human genes, are essential to producing many biochemical building blocks, such as 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 CYP P450 genes can result in the inability to properly metabolize medications and other substances, leading to increased levels of toxic substances in the body.

Thiopurine methyltransferase (TPMT) is an enzyme that methylates azathioprine, mercaptopurine and thioguanine into active thioguanine nucleotide metabolites. Azathioprine and mercaptopurine are used for treatment of nonmalignant immunologic disorders; mercaptopurine is used for treatment of lymphoid malignancies; and thioguanine is used for treatment of myeloid leukemias.

Dihydropyrimidine dehydrogenase (DPD), encoded by the gene DPYD, is a rate-limiting enzyme responsible for fluoropyrimidine catabolism. The fluoropyrimidines (5-fluorouracil and capecitabine) are drugs used in the treatment of solid tumors, such as colorectal, breast, and aerodigestive tract tumors.

A variety of cell surface proteins, such as antigen-presenting molecules and other proteins, are encoded by the human leukocyte antigen genes (HLAs). HLAs are also known as major histocompatibility complex (MHC).

Regulatory Status 
Diagnostic genotyping tests for certain drug metabolizing enzymes are FDA-approved. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. 

Currently, there are over 10 other FDA-approved tests for the drug metabolizing enzymes that are nucleic acid-based tests including xTAG CYP2D6 Kit v3 and XTAG CYP2C19 KIT V3 (Luminex Molecular Diagnostics Inc.), Spartan RX CYP2C19 Test System (Spartan Bioscience Inc.), Verigene CYP2C19 Nucleic Acid Test (Nanosphere Inc.), INFINITI CYP2C19 Assay (AutoGenomics Inc.), Invader UGT1A1 (Third Wave Technologies Inc.), 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) (FDA, 2018a).

FDA Notes
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 (FDA, 2018b).

The current list of pharmacogenomic biomarkers in drug labeling by FDA contains a total of 92 medications that have genotypes related to metabolism dosage recommendations or warnings. These medications are involved in different therapeutic areas and the list includes the following genes and medications:

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 58 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. Lofexidine was added in the most recent update of June 2018.

CYP3A5: Prasugrel (FDA, 2018c)
TMPT: Thioguanine
NUDT15: Thioguanine (FDA, 2018c).

FDA Recommendations
The FDA package insert for Plavix (clopidogrel) carries the following “Black Box” warning: “The effectiveness of Plavix results from its antiplatelet activity which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed 'CYP2C19 poor metabolizers'). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.” (FDA, 2016)

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. (FDA, 2008)

The Coumadin (warfarin) highlights of prescription information notes that “the appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Genetic factors (CYP2C9 and VKORC1 genotypes).” Although dosage suggestions based on CYP2C9 and VKORC1 genotypes are provided in the package insert, the requirement for genetic testing is not included (FDA).

The eligibility and dosing of Eliglustat is dependent on cytochrome P450 CYP2D6 genotype as eliglustat is extensively metabolized by CYP2D6. The FDA contraindicates this medication in the following patients due “to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac Intervals”:

EMs of CYP2D6

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Moderate or severe hepatic impairment
• Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor

IMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Taking a strong CYP3A inhibitor
• Any degree of hepatic impairment

PMs

• Taking a strong CYP3A inhibitor
• Any degree of hepatic impairment (FDA, 2014) 

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. Testing for the CYP2D6 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing:
   1. Amphetamine
   2. Aripiprazole
   3. Aripiprazole Lauroxil
   4. Atomoxetine
   5. Brexpiprazole
   6. Carvedilol
   7. Cevimeline
   8. Clozapine
   9. Codeine
   10. Desipramine
   11. Deutetrabenazine
   12. Eligustat
   13. Fluvoxamine
   14. Gefitinib
   15. Iloperidone
   16. Lofexidine
   17. Meclizine
   18. Metoclopramide
   19. Nortriptyline
   20. Oliceridine
   21. Ondansetron
   22. Paroxetine
   23. Perphenazine
   24. Pimozide
   25. Pitolisant
   26. Propafenone
   27. Tamoxifen
   28. Tetrabenazine
   29. Thioridazine
   30. Tolterodine
   31. Tramadol
   32. Tropisetron
   33. Valbenazine
   34. Venlafaxine
   35. Vortioxetine
2. Testing for the CYP2D6 and CYP2C19 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Amitriptyline
   2. Clomipramine
   3. Doxepin
   4. Imipramine
   5. Trimipramine
3. Testing for the CYP2C19 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Brivaracetam
   2. Citalopram
   3. Clobazam   
   4. Clopidogrel     
   5. Dexlansoprazole (see Note 1)
   6. Escitalopram
   7. Flibanserin
   8. Lansoprazole (see Note 1)
   9. Omeprazole (see Note 1)
   10. Pantoprazole (in pediatric individuals) (see Note 1)
   11. Sertraline  
   12. Voriconazole (see Note 1)
4. Testing for the CYP2C9 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Celecoxib
   2. Dronabinol
   3. Erdafitinib
   4. Flurbiprofen
   5. Lornoxicam
   6. Meloxicam
   7. Piroxicam
   8. Siponimod
   9. Tenoxicam
5. Testing for the CYP2C9, CYP4F2, VKORC1, and rs12777823 genotype once per lifetime is considered MEDICALLY NECESSARY for individuals being considered for Warfarin therapy.
6. Testing for the TPMT and NUDT15 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Azathioprine
   2. Mercaptopurine
   3. Thioguanine
7. Testing for the DPYD genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Capecitabine
   2. Flucytosine
   3. Fluorouracil
   4. Tegafur
8. 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 medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. HLA-B*57:01 before treatment with Abacavir
   2. HLA-B*58:01 before treatment with Allopurinol
   3. HLA-B*15:02 for treatment with Oxcarbazepine
   4. HLA-B*15:02 and HLA-A*31:01 for treatment with Carbamazepine
9. Testing for the CYP2C9 and HLA-B*15:02 genotype 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 this medication, to aid in therapy selection and/or dosing:
   1. Phenytoin/Fosphenytoin
10. Testing for the G6PD genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
    1. Pegloticase
    2. Primaquine
    3. Rasburicase
    4. Tafenoquine
11. Testing for the following genotypes once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing:
    1. BCHE for treatment with mivacurium or succinylcholine
    2. CFTR for treatment with Ivacaftor, Elexacaftor and Tezacaftor, Ivacaftor and Lumacaftor, or Ivacaftor and Tezacaftor
    3. CYP2B6 for treatment with Efavirenz
    4. CYP3A5 for treatment with Tacrolimus
    5. IFNL3 treatment with Peginterferon alfa-2a, Peginterferon alfa-2b or Ribavirin
    6. NAT2 for treatment with Amifampridine or Amifampridine Phosphate
    7. UGT1A1 for treatment with Atazanavir, Belinostat, Irinotecan, Nilotinib, Pazopanib, or Sacituzumab govitecan-hziy
12. Testing for the RYR1 and CACNA1S genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for the use of depolarizing muscle relaxants, such as succinylcholine, or halogenated volatile anesthetics.
13. 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.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

1. The following pharmacogenetic testing is considered NOT MEDICALLY NECESSARY:
   1. Genotyping for any medication therapy more than once per lifetime (please see policy guideline).*
   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.
   5. Pharmacogenetic panel testing for individuals not being considered for any of the above conditions.
2. All other single nucleotide polymorphism (SNP) testing, either as individual SNPs or as a panel of SNPs, is considered NOT MEDICALLY NECESSARY for all indications. The list of SNPs includes, but is not limited to, the following:
   1. 5HT2C (serotonin receptor)
   2. 5HT2A (serotonin receptor)
   3. SLC6A4 (serotonin transporter)
   4. DRD1 (dopamine receptor)
   5. DRD2 (dopamine receptor)
   6. DRD4 (dopamine receptor) 
   7. DAT1 or SLC6A3 (dopamine transporter)
   8. DBH (dopamine beta-hydroxylase)
   9. COMT (catechol-O-methyl-transferase)
   10. MTHFR (methylenetetrahydrofolate reductase)
   11. γ-Aminobutyric acid (GABA) A receptor
   12. OPRM1 (µ-opioid receptor)
   13. OPRK1 (κ-opioid receptor)
   14. TYMS
   15. UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
   16. Cytochrome P450 genes: CYP3A4, CYP1A2

*Policy Guideline
Genotyping once per lifetime

Any gene should be tested once per lifetime regardless of the indication (an exception 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 NOT MEDICALLY NECESSARY. 

Note 1: Pharmacogenetic testing for proton pump inhibitor therapies (PPIs) ONLY MEETS COVERAGE CRITERIA if the patient has an active H. pylori infection.

Table of Terminology 

Rationale
Genetic variations play a potentially large role in an individual’s response to medications. However, drug metabolism and responses are affected by many other factors, including age, sex, interactions with other drugs, and disease states (Tantisira & Weiss, 2020). Nonetheless, 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 potentially even more so than clinical variables such as age and organ function (Kapur et al., 2014; Ting & Schug, 2016). Genetic variation can influence pharmacodynamic factors through variations affecting drug target receptors and downstream signal transduction, or pharmacokinetic factors, affecting drug metabolism and/or elimination (Tantisira & Weiss, 2020).

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. This system may serve to “activate” an inactive form of a drug, as well as inactivate and/or clear 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. In some cases, alleles can be highly correlated with ethnic background. Generally, there are three categories of metabolizer; ultra-rapid metabolizers, normal metabolizers, and poor metabolizers (Tantisira & Weiss, 2020).

Due to the variations in enzyme activity conferred by allelic differences, some CYP 450 alleles are associated with an 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 regarding clinical use for drug selection and/or dosing. Phenotypes, such as CYP2D6, CYP2C9 and CYP2C19, have been associated with the metabolism of several therapeutic drugs, and various alleles of the CYP450 gene 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 specific CYP 450 enzyme, lower activity may yield less of the biologically active drug, which could result in lower drug efficacy. Individuals considered 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 the active drug, potentially causing unwanted side effects. Due to these differences in enzyme activity, some alleles are associated with a higher risk of adverse outcomes depending on the drug prescribed (Tantisira & Weiss, 2020).

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 a higher circulating drug concentration. CYP2C9*2 and CYP2C9*3 are the most common variants with reduced activity. Variations in a second gene, VKORC1, also can impact warfarin’s effectiveness. This gene codes for the enzyme that is the target for warfarin. Genotypes resulting in reduced metabolism may need a higher dose to achieve the desired efficacy (Tantisira & Weiss, 2020).

CYP2C19
Clopidogrel (brand name Plavix) is used to inhibit platelet aggregation and is given as a pro-drug 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 (Tantry et al., 2021). Tuteja et al. (2020) studied CYP2C19 genotyping to guide antiplatelet therapy. A total of 504 participants contributed to this study, with only 249 participants genotyped. The authors noted that genotyping results “significantly influenced antiplatelet drug prescribing; however, almost half of CYP2C19 LOF [loss-of-function] carriers continued to receive clopidogrel. Interventional cardiologists consider both clinical and genetic factors when selecting antiplatelet therapy following PCI [percutaneous coronary intervention] (Tuteja et al., 2020).”

CYP2D6
Tetrabenazine (brand name Xenazine) is used in the treatment of chorea associated with Huntington disease. This drug is metabolized for clearance primarily by CYP2D6. Poor metabolizers are considered to be those individuals with impaired CYP2D6 function, and dosing is often influenced by how well a patient metabolizes the drug. For example, a poor metabolizer will often have a maximum dose of 50 mg daily whereas an extensive metabolizer has a maximum dose of 100 mg daily (Suchowersky, 2021).

Tamoxifen, a drug commonly used for the treatment and prevention of recurrence of estrogen receptor positive breast cancer, is metabolized by CYP2D6. Polymorphisms of CYP2D6 have been noted to affect the efficacy of tamoxifen by affecting the amount of active metabolite produced. Endoxifen, which is the primary active metabolite of tamoxifen, has a 100-fold affinity for the estrogen receptor compared to tamoxifen, but poor metabolizers have been demonstrated to show lower than expected levels of plasma endoxifen (Ahern et al., 2017).

Codeine, which is commonly used to treat mild to moderate pain, is metabolized to morphine, a much more powerful opioid, by CYP2D6. Individuals with varying CYP2D6 activity may see negative side effects or a shorter duration of pain relief. The effect is significant enough to have caused fatalities in unusual metabolizers; for instance, an ultra-rapid metabolizing toddler was reported to have passed away after being given codeine for a routine dental operation (Kelly et al., 2012; Tantisira & Weiss, 2020).

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 with 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 inherit both active TPMT alleles will have a lower risk of myelosuppression. Therefore, genotyping for TPMT is critical before starting therapy with thiopurine drugs (Relling et al., 2011).

DPYD
The dihydropyrimidine dehydrogenase (DPYD) gene encodes for the rate-limiting enzyme dihydropyrimidine dehydrogenase, which is involved in catabolism of fluoropyrimidine drugs used in the treatment of solid tumors. Decreased DPD activity increases the risk for severe or even fatal drug toxicity when patients are being treated with fluoropyrimidine drugs. Numerous genetic variants in the DPYD gene have been 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 variant in Europeans is HapB3 with a c.1129 – 5923C>G DPYD variant which 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%). Approximately 7% of Europeans carry at least one decreased function DPYD variant. In people with African ancestry, the most common variant is c.557A>G (rs115232898, p.Y186C) and is relatively common (3% – 5% carrier frequency). Other DPYD decreased function variants are rare. Therefore, most available genetic tests focus on identifying the most common variants with well-established risk: (c.190511G>A, c.1679T>G, c.2846A>T, c.1129 – 5923C>G) (Amstutz et al., 2018).

TYMS
TYMS (thymidylate synthetase) encodes an enzyme necessary for thymidine production. As with DPYD, TYMS is thought to be involved with the toxicity of fluoropyrimidines. Fluorouracil (FU)’s primary metabolite inhibits thymidylate synthetase by forming a stable complex with thymidylate synthetase and folate, thereby blocking activity of the enzyme. Polymorphisms in the TYMS gene further affect the interaction between TYMS and FU, potentially increasing the toxicity of FU. Genotyping of TYMS prior to treatment with FU or capecitabine has been suggested for clinical practice, but data has been varied (Krishnamurthi & Kamath, 2022).

Castro-Rojas et al. (2017) evaluated TYMS genotypes as predictors of both clinical response and toxicity to fluoropyrimidine-based treatment for colorectal cancer. A total of 105 patients were genotyped. The authors noted that while the 2R/2R genotype was associated with clinical response (odds ratio = 3.45), the genotype was also associated with severe toxicity (odds ratio = 5.21). The genotype was thought to be associated with low TYMS expression. The authors further identified the rs2853542 and rs151264360 alleles to be independent predictors of response failure to chemotherapy (Castro-Rojas et al., 2017).

HLAs
Human Leukocyte antigens (HLAs) are 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, 2021).

An article published by van der Wouden et al. (2019) reports on the development of the new PGx-Passport panel (pre-emptive pharmacogenetics-passport panel), which is able to test “58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1)”; this standardized panel is based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines and will help physicians to optimize drug prescription in 49 common drugs. It is recommended by the authors that commercial and hospital laboratories utilize this panel for personalized medicinal purposes. Drug optimization in the 49 commonly prescribed drugs includes ten antidepressants, five immunosuppressants, five anti-cancer drugs, four anti-infectives, four anticoagulants, four antiepileptics, four antipsychotics, three proton pump inhibitors, two anti-arrhythmics, two analgesics, two antilipidemics, one antihypertensive, one psychostimulant, one anticontraceptive and one Gaucher disease drug (van der Wouden et al., 2019).

Proprietary Testing
Due to the increase in pharmacogenetic genotyping, proprietary gene panels have become commercially available. Panels encompassing the most common genes that influence drug metabolism have increased in usage. For example, Myriad’s new proprietary panel “GeneSight” proposes it can “predict poorer antidepressant outcomes and to help guide healthcare providers to more genetically optimal medications,” thereby leading to better patient outcomes. The test assesses every known metabolic pathway (CYP450 or otherwise) for a given drug and their metabolites, as well as the pharmacodynamic activity of the compound and its metabolites, any FDA information on that drug, and other validated research on the relevant alleles; this information is then integrated with the genetic test results. This allows the test to categorize the 55 FDA-approved medications into three categories: “green (use as directed), yellow (some moderate gene-drug interaction) and red (significant gene-drug interaction).” Myriad states that this allows every metabolic pathway of a drug to be evaluated instead of the “one gene, one drug” view. Other GeneSight variations, such as GeneSight Psychotropic used for psychotropic medications, exist as well (Myriad, 2016, 2019). Still, other companies such as Mayo Clinic and Sema4 have developed their own pharmacogenetic panels, each with individually chosen analytes (Mayo, 2019; Sema4, 2019).

Benitez et al. (2018) assessed the cost-effectiveness of pharmacogenomics in treating psychiatric disorders. The authors compared 205 members that received guidance from GeneSight’s Psychotropic to 478 members that received “treatment-as-usual” (TAU). Reimbursement costs were calculated over the 12 months pre- and post-index event periods. The authors found a total post-index cost savings of $5,505, which was equivalent to a savings of $0.07 per-member-per-month (PMPM). The authors also evaluated the savings at different adoption rates of the GeneSight test. At 5% adoption, commercial payer savings was calculated at $0.02 PMPM and at 40% adoption, savings was $0.15 PMPM (Benitez et al., 2018).

The AmpliChip^® (Roche Molecular Systems Inc.) is the FDA-cleared test for CYP450 genotyping. This test genotypes CYP2D6 and CYP2C19. From the FDA website: “The AmpliChip CYP4502C19 Test is designed to identify specific nucleic acid sequences and query for the presence of certain known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wild-type or mutant sequences (FDA, 2005).” The analytical accuracy was evaluated at 99.6%, or 806 of 809 samples identified correctly. This test assesses a total of 30 alleles, 3 for CYP219 and 27 for CYP2D6 (FDA, 2005).

The OneOme RightMed Pharmacogenomic Test analyzes more than 100 variants in 27 genes to study how a patient may respond to certain medications. The test covers CYP1A2, CYP2B6, CYP2C Cluster, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, COMT, DPYD, DRD2, F2, F5, GRIK4, HLA-A, HLA-B, HTR2A, HTR2C, IL28B (IFNL4), MTHFR*, NUDT15, OPRM1, SLC6A4, SLCO1B1, TPMT, UGT1A1, and VKORC1 (OneOme, 2021). Analytical validity of the test was assessed by comparing RightMed test results with bi-directional Sanger sequencing results, which resulted in 100% concordance. The RightMed test detects CYP2D6 deletions, duplications, and hybrid alleles, but cannot differentiate duplications in the presence of a deletion (GTR, 2017).

Clinical Utility and Validity
A study evaluating GeneSight Psychotropic’s clinical utility was performed by Greden et al. (2019); a total of 1,167 patients with major depressive disorder were split into two randomized groups: treatment as usual (TAU) and pharmacogenetic-guided. Medications were classified as “congruent” ("use as directed" or "use with caution" test categories) or “incongruent” ("use with increased caution and with more frequent monitoring" test category) with test results. After 8 weeks, the authors found a statistically significant improvement in response and remission; 26% for the pharmacogenetic arm compared 19.9% for TAU and 15.3% for remission compared to 10.1% for TAU (Greden et al., 2019). The authors concluded that pharmacogenetic testing did not improve results, but significantly improved response and remission rates for “difficult-to-treat depression patients over standard of care” (Greden et al., 2019).

Kekic et al. (2020) studied genetic variants that commonly affect supportive care medications, which include, antidepressants, antiemetics, and analgesics, used in oncology practice. 196 cancer patients were genotyped using a multi-gene panel, OneOme RightMed. The panel assessed 27 genes, including CYP2C9, CYP2C19, CYP2D6, CYP3A4, COMT, OPRM1, GRIK4, HTR2A, SLC6A4, associated with pain medications, antidepressants, and antiemetics. Of the 196 patients, 19.9% had prostate cancer, 17.9% had colorectal cancer, 14.8% had melanoma, and 47.4% had other cancer types. All 196 patients had at least one actionable polymorphism related to these supportive care medications, specifically, in CYP2C19 and CYP2D6. 67.3% of the patients had other than normal CYP2D6 metabolizer phenotype and 57.1% had other than normal CYP2C19 metabolizer phenotype. Based on the results, 37 patients were recommended an alternative analgesic, 9 were recommended an alternative antiemetic, and 51 were recommended an alternative anti-depressant (Kekic et al., 2020).

Plumpton et al. (2019) evaluated the cost-effectiveness of panel tests with various pharmacogenes. The constructed multigene panel included HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T), and HLA-DQB1 (126Q), which are involved with various treatments (abacavir, carbamazepine, et al). The constructed multigene panel was found to provide a cost savings of $491 if all findings for all alleles were acted on, regardless of an allele’s individual cost-effectiveness. Testing for patients eligible for abacavir (HLA-B*57:01) and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)) was found to be cost-effective. However, testing for patients eligible for allopurinol (HLA-B*58:01) was not found to be cost-effective. Furthermore, testing for HLA-A*31:01 for carbamazepine was found to be cost-effective, but not testing for HLA-B*15:02 (Plumpton et al., 2019).

Braten et al. (2020) researched the impact of CYP2C19 genotyping on the antidepressant drug sertraline, which is metabolized by the polymorphic CYP2C19 enzyme. A total of 1,202 patients participated and submitted 2190 sertraline serum samples. All patients were categorized based on CYP2C19 genotype-predicted phenotype subgroups; these groups include normal (NM), ultra-rapid (UM), intermediate (IM), and poor metabolizer (PM). Serum samples showed that CYP2C19 IM and PM patients had significantly higher sertraline concentrations compared to NMs; “Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients (Braten et al., 2020).”

Roscizewski et al. (2021) conducted a retrospective observational study to determine what effect pharmacogenomic testing had on “treatment decisions in patients with depressive symptoms in an interprofessional primary care setting.” From April 2019 to March 2021, they identified 78 patients who underwent pharmacogenomic testing for psychotropic medications. They found that 53.8% of patients “experienced a change to their antidepressant regiment after [pharmacogenomic] testing,” with the most cited change being addition of another antidepressant, followed by switching the antidepressant, then increased dose. This demonstrated how pharmacogenomic testing could be useful in informing clinical decision making at the beginning of treatment or “in those who experience an inadequate response to their prescribed regimen” and ensuring optimal patient recovery.

Stevenson et al. (2021) aimed to assess the potential impact of multigene pharmacogenomic testing among those hospitalized with COVID-19 in the United States. Through a cross-sectional analysis with electronic health records, researchers “characterized medication orders, focusing on medications with actionable guidance related to 14 commonly assayed genes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, HLA-A, HLA-B, IFNL3, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1).” From their cohort, they found that 64 unique medications with pharmacogenomic guidance were ordered at least once, and about 89.7% of patients “had at least one order for a medication with PGx guidance and … (23.1%) had orders for 4 or more actionable medications.” Through a simulation analysis, they estimated that “17 treatment modifications per 100 patients would be enabled if [pharmacogenomic] results were available,” and that the genes CYP2D6 and CYP2C19 were responsible for most of the treatment modifications. Medications most affected included ondansetron, oxycodone, and clopidogrel. With additional investigations that support these findings, pharmacogenomic testing would better inform the curation of individualized treatment plans for patients suffering from severe COVID-19.

Clinical Pharmacogenetics Implementation Consortium (CPIC)
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) (CPIC, 2019).

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

CYP2C9 Genotypes 

CYP2D6 Genotype 

CYP2B6 Genotypes 

CYP2C19 Genotype 

CYP2D6 and CYP2C19 Genotypes (Caudle et al., 2020; Hicks et al., 2017) for Amitriptyline, Clomipramine, Doxepin, Imipramine, and Trimipramine

TPMT Genotype 

NUDT15 Genotype

DPYD Genotypes 

HLA-B Genotypes 

Additional Genotypes 

CPIC notes that evidence for TYMS testing is unclear or weak and have assigned TYMS a “D” level recommendation. CPIC does not recommend any change in prescription based on TYMS genotype (CPIC, 2021).

American College of Medical Genetics and Genomics (ACMG)
ACMG notes that CYP2C9 and VKORC1 testing may be useful for assessing unusual responses to warfarin, but cannot recommend for or against routine genotyping (ACMG, 2007).

American College of Cardiology Foundation (AACF) and the American Heart Association (AHA) Joint Guidelines
A report by the ACCF and the AHA on genetic testing for selection and dosing of clopidogrel provided the following recommendations for practice: 

• “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.”
• “The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined (e.g., the importance of CYP2C19*2 versus *3 or *4 for a specific patient), and the frequency of genetic variability differs among ethnic groups.”
• “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 evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. There is no information that routine testing improves outcome in large subgroups of patients. In addition, the clinical course of the majority of patients treated with clopidogrel without either genetic testing or functional testing is excellent. Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism (“poor metabolizers”) may be considered before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, among others, patients undergoing elective high-risk PCI procedures (e.g., treatment of extensive and/or very complex disease). If such testing identifies a potential poor metabolizer, other therapies, particularly prasugrel for coronary patients, should be considered. (Holmes et al., 2010).

American Academy of Neurology (AAN)
The AAN published a position paper on the use of opioids for chronic non-cancer pain. Regarding pharmacogenetic testing, the guidelines state “genotyping to determine whether response to opioid therapy can/should be more individualized will require critical original research to determine effectiveness and appropriateness of use” (Franklin, 2014).

American Association for Clinical Chemistry (AACC) Academy Laboratory Medicine Practice Guidelines
AACC Academy issued laboratory medicine practice guidelines on using clinical laboratory tests to monitor drug therapy in pain management. Their guidelines have a total of 26 recommendations and 7 expert opinions. Regarding pharmacogenetic testing for pain management, they stated in the recommendation #20 (Level A, II) that “while the current evidence in the literature doesn’t support routine genetic testing for all pain management patients, it should be considered to predict or explain variant pharmacokinetics, and/ or pharmacodynamics of specific drugs as evidenced by repeated treatment failures, and/or adverse drug reactions/toxicity (AACC, 2017).”

American Family Physician (AAFP)
The AAFP has published guidelines on pharmacogenetics: using genetic information to guide drug therapy. CPIC guidelines are cited for many medication/allele combinations in this article. The recommendations by the AAFP are listed in the table below taken from Chang et al. (2015):

Dutch Pharmacogenetics Working Group (DPWG)
The DPWG has published guidelines for the gene-drug interaction of DPYD and fluoropyrimidines. Conclusions state that “four variants have sufficient evidence to be implemented into clinical care: DPYD*2A (c.1905+1G>A, IVS14+1G>A), DPYD*13 (c.1679T>G), c.2846A>T and c.1236G>A (in linkage disequilibrium with c.1129–5923C>G). The current guideline only reports recommendations for these four variants; no recommendations are provided for other variants in DPYD or other genes (Lunenburg et al., 2019).”

Food and Drug Administration
The FDA published several tables of pharmacogenetic associations with “sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (i.e., affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events”.

The table below lists associations “for which the data support therapeutic management recommendations” (FDA, 2021b).

The table below lists associations “for which the data indicate a potential impact on safety or response” (FDA, 2021b).  

The International Society of Psychiatric Genetics
The International Society of Psychiatric Genetics (ISPG) released recommendations on the use of pharmacogenetic testing to guide psychiatric treatment. ISPG recommends that pharmacogenetic testing should be used as a decision-support tool. HLA-A and HLA-B testing is recommended before the use of carbamazepine and oxcarbazepine. CYP2C19 and CYP2D6 testing would be beneficial for those who experienced an inadequate response or adverse reaction to a previous antidepressant or antipsychotic medication (ISPG, 2019).

The American Academy of Child and Adolescent Psychiatry
AACAP does not recommend the use of pharmacogenetic testing to select psychotropic medications for children and adolescents (AACAP, 2020)

Association for Molecular Pathology PGx Working Group (AMP)
AMP released clinical practice guidelines to define a minimum set of CYP2C19 allele variants that should be included in the pharmacogenomic genotyping assay. Tier 1 represents alleles that have been shown to affect drug response and should be included, while Tier 2 represents alleles which meet at least one but not all the criteria for inclusion in Tier 1 and are considered optional for inclusion in expanded clinical genotyping panels. Those in Tier 1 include alleles *2, *3, and *17. The following CYP2C19 alleles were recommended as Tier 2: *4A, *4B, *5, *6, *7, *8, *9, *10, and *35 (Pratt et al., 2018). Regarding CYP2C9 variant alleles, Tier 1 alleles include CYP2C9 *2, *3, *5, *6, *8, and *11. The following CYP2C9 alleles are recommended for inclusion in Tier 2: CYP2C9*12, *13, and *15 (Pratt et al., 2019). For testing genes and alleles specific to warfarin, AMP recommends including VKORC1 c.-1639G>Ain Tier 1 and VKORC1 c.196G>A and c.106G>A in Tier 2 (Pratt et al., 2020). In a joint recommendation endorsed by the AMP, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy, CYP2D6 variant alleles were elucidated. Tier 1 alleles include CYP2D6 *2 to *6, *9, *10, *17, *29, and *41. Tier 2 CYP2D6 alleles include CYP2D6 *7, *8, *12, *14, *15, *21, *31, *40, *42, *49, *56, and *59, and hybrid genes containing portions of CYP2D6 and CYP2D7 (Pratt et al., 2021). These recommendations should help to standardize testing and genotyping concordance among laboratories.

European Medicines Agency
EMA released recommendations on DPD testing before treatment with fluorouracil, capecitabine, tegafur, and flucytosine. EMA recommends testing for the lack of DPD before starting cancer treatment with fluorouracil, capecitabine, or tegafur. Patients who completely lack DPD should not be given these medications. For patients with partial deficiency, the physician may consider beginning treatment at a lower dose and terminating treatment if severe side effects occur. These recommendations do not apply to fluorouracil medications used for skin conditions or flucytosine used for fungal infection (EMA, 2020).

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