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Pharmacogenomics: The Use of Genetics in Guiding Pharmacologic Therapy



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September 2012

Background

Pharmacogenomics (also known as pharmacogenetics) is a component of individualized medicine that focuses on how genetic factors influence individual responses to different medications that may affect drug efficacy, drug side effects, and adverse events related to drug therapy. This area of study can play an important role in identifying responders and nonresponders to medications and thus avoid adverse events and optimize drug dose.

Figure 1

Drug labels may contain information on genomic biomarkers and can describe a number of potential clinical events. These may include drug exposure and clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms of drug action, and polymorphic drug target and disposition genes. Some examples of FDA-approved drugs with pharmacogenomic-related label information are shown in Table 1. In this article, we focus on some of the FDA-approved drugs that have boxed warnings or other label warnings or precautions related  to pharmacogenomics.

Genetic Marker Therapeutic Area Drugs
CYP2C9 Analgesics
Psychiatry
Hematology
Celecoxib
Fluvoxamine
Warfarin
CYP2C19 Musculoskeletal
Psychiatry
Neurology
Cardiovascular
Gastroenterology
Carisoprodol
Citalopram, Diazepam, Fluvoxamine
Clobazam
Clopidogrel, Prasugrel
Esomeprazole, Omeprazole, Pantoprazole
CYP2D6 Psychiatry
Cardiovascular
Derm and Dental
Analgesics
Citalopram, Fluoxetine, Paroxetine, Venlafaxine, (numerous)
Carvedilol, Metoprolol, Propranolol, (others)
Cevimeline
Codeine
HLA-B*1502 Neurology Carbamazepine, Phenytoin
HLA-B*5701 Antiretrovirals Abacavir
UGT1A1 Oncology
Pulmonary
Irinotecan, Nilotinib
Indacaterol
VKORC1 Hematology Warfarin

Table 1. FDA-Approved Drugs with Pharmacogenomic-Related Label Information

Pharmacogenomic Applications

Clopidogrel

In March 2010, the FDA issued a label warning update for response to clopidogrel by CYP2C19 enzyme poor metabolizers. Clopidogrel, or Plavix, is a commonly used antiplatelet drug that is administered as an inactive prodrug and metabolized to its active form by cytochrome P450 (CYP) enzymes. Clopidogrel is used to reduce atherosclerotic events, such as myocardial infarction, stroke, and vascular death, in patients with acute coronary syndrome (ACS) and/or following percutaneous coronary intervention (PCI). It is often given as an alternative to aspirin or in combination with aspirin (ie, dual-antiplatelet therapy). Response to clopidogrel is highly variable. The drug is efficacious in some individuals and not in others, due to a number of variables that may include underdosing, interactions with CYP inhibitors and substrates (eg, lipophilic statins, calcium antagonists, proton-pump inhibitors), and genetics.

As mentioned, clopidogrel is given as a prodrug. It is metabolized to its active form by CYP2C19 and other enzymes. The CYP2C19 gene has several recognized loss-of-function alleles, but the 2 alleles that have been studied the most in relation to clopidogrel are *2 and *3. These alleles are associated with lower levels of the active metabolite of clopidogrel and a marked decrease in platelet responsiveness to the drug (ie, higher on-treatment platelet aggregation). CYP2C19 loss-of-function alleles have been associated with an increased rate of subsequent cardiovascular events and death in patients taking clopidogrel. For example, the TRITON-TIMI 38 study by Mega and colleagues1 showed that patients who had a CYP2C19 loss-of-function allele and were taking clopidogrel had a relative 53% increased risk of death from cardiovascular causes, myocardial infarction, or stroke, and a 3-fold increased risk of stent thrombosis compared with patients without CYP2C19 loss-of-function alleles who were taking clopidogrel. Higher risks for cardiovascular events and stent thrombosis have been demonstrated for both heterozygote and homozygote *2 carriers who are given clopidogrel. This study and others have demonstrated that individuals with CYP2C19 loss-of-function alleles who are taking clopidogrel might not receive benefit (or may receive less benefit) from the drug.

CYP2C19 gene testing for predicting response to clopidogrel is performed clinically. However, the widespread adoption of this testing has not yet occurred and may be due, in part, to the lack of recommendation for routine use of genotyping for screening purposes as per the 2011 guidelines for PCI by the ACCF/AHA/SCAI task force2 and other clinical groups. Nonetheless, some would argue that there is sufficient evidence to provide this testing for certain groups of patients, such as those undergoing coronary stenting. It is anticipated that large, randomized, prospective clinical outcomes trials are likely needed before clinical adoption of this testing will be more fully embraced.

Mayo Medical Laboratories offers a test that can assist in predicting an individual’s response to clopidogrel. 2C19S/60439 Cytochrome P450 2C19 Genotype by Sequence Analysis is a sequencing-based assay that detects the presence of *2, *3, *4, *6, *7, *8, and *17, as well as any other rare variants that may occur in the regions sequenced. This test may also be useful for psychiatry applications.

Warfarin

Warfarin has 2 FDA-issued label warnings. The first was issued in August 2007 in reference to warfarin sensitivity in CYP2C9 poor metabolizers. The second warfarin label update was issued in January 2010, and included the effect of a second gene, VKORC1, as well as a table with pharmacogenomic-guided dosing ranges for the drug.

Warfarin, an anticoagulant used for the short- and long-term management of thromboembolic disorders, is one of the most commonly prescribed drugs. Warfarin can be challenging to dose appropriately,  and the prothrombin time (INR) must be maintained in a narrow therapeutic range. If individuals are given too much warfarin, they can have an elevated INR and be at risk for major bleeding complications. If individuals are not given enough warfarin, they can have subtherapeutic levels and be at risk for thrombotic complications.

VKORC1
CYP2C9
*1/*1
*1/*2
*1/*3
*2/*2
*2/*3
*3/*3
GG 5–7 mg 5–7 mg 3–4 mg 3–4 mg 3–4 mg 0.5–2 mg
AG 5–7 mg 3–4 mg 3–4 mg 3–4 mg 0.5–2 mg 0.5–2 mg
AA 3–4 mg 3–4 mg 0.5–2 mg 0.5–2 mg 0.5–2 mg 0.5–2 mg

Table 2. Three Ranges of Expected Maintenance Coumadin Daily Doses Based on CYP2C9 and VKORC1 Genotypes
Abbreviations: GG: normal VKORC1 genotype; AG: variant VKORC1 genotype; AA: variant VKORC1 genotype;*1/*1: normal CYP2C9 gene alleles; *1/*2: variant CYP2C9 gene alleles; *1/*3: variant CYP2C9 gene alleles; *2/*2: variant CYP2C9 gene alleles; *2/*3: variant CYP2C9 gene alleles;*3/*3: variant CYP2C9 gene allele

There are 2 major genes involved in warfarin pharmacogenomics: CYP2C9 and VKORC1. Two common star alleles in the CYP2C9 gene, known as *2 and *3, lead to decreased enzymatic activity and warfarin sensitivity. The second gene is VKORC1, which encodes for the vitamin K epoxide reductase complex, subunit 1. A common VKORC1 promoter variant, which occurs at position c.-1639G>A, can lead to warfarin sensitivity or mild warfarin resistance, depending on which combinations of G and A alleles are present. Table 2 displays genotype-guided dosing recommendations based on the combination of CYP2C9*2 and *alleles and VKORC1 promoter polymorphism alleles3. The allele frequencies for CYP2C9*2 and *3 and VKORC1 in different ethnic groups are shown in Table 3. It is interesting to note that the majority of warfarin sensitivity in the Asian population is thought to be due to variability at the VKORC1 promoter.

  CYP2C9*2 CYP2C9*3 VKORC1
–1639G>A
Caucasian 8%–13% 6%–10% 42%
Asian 2%–5% <1% 89%
African American <1% 1%–4% 8%
Table 3. Allele Frequency in Ethnic Groups
Abbreviations: CYP2C9*2: variant CYP2C9 gene allele; CYP2C9*3: variant CYP2C9 gene allele; VKORC1 -1639G>A: VKORC1 genetic polymophism

A 2010 study4 evaluated hospitalization rates for patients beginning warfarin therapy with genotype-guided dosing as compared to historical controls without genotype-guided dosing. The study demonstrated that patients whose warfarin dosing was guided by genotype had 31% fewer hospitalizations for any reason. In addition, hospital admissions for thromboembolism or bleeding were 28% less frequent in the genotyped group.

Mayo Medical Laboratories offers tests that can be used as an aid for predicting an individual’s sensitivity to warfarin. These tests are WARFP/60529 Warfarin Sensitivity Genotype by Sequence Analysis, Blood and WARFO/60341 Warfarin Sensitivity Genotype by Sequence Analysis, Saliva. They are sequencing-based assays that detect the presence of CYP2C9*2,*3, *5, and *6, the promoter variant in VKORC1, and any other rare variants that may occur in the regions sequenced.

Psychiatric Applications

Another group of drugs with pharmacogenomic-related label information are those used in psychiatric applications. Most psychotropic medications are metabolized by cytochrome enzymes, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and some benzodiazepines and antipsychotics. The major cytochrome P450 enzymes, or CYPs, involved in metabolism of these drugs are CYP2D6, CYP1A2, CYP3A4, CYP2C9, and CYP2C19. Psychotherapeutic pharmacogenomic testing is available for 3 major CYPs: CYP2D6, CYP2C9 and CYP2C19. Some of the psychotherapeutics metabolized by these enzymes are listed in Table 4.

CYP2C9 CYP2C19 CYP2D6
Amitriptyline Amitriptyline Amitriptyline
Fluvoxamine Citalopram Clomipramine
Phenytoin Diazepam Desipramine
  Escitalopram Fluoxetine
  Fluoxetine Fluvoxamine
  Imipramine Haloperidol
  Phenytoin Imipramine
  Venlafaxine Nortriptyline
    Paroxetine
    Venlafaxine
    Amphetamines
    Aripiprazole
    Atomoxetine
Table 4. Psychotherapeutic Drugs Metabolized by the Cytochrome P450 (CYP) Enzyme Family

CYP2D6 is involved primarily or substantially in the metabolism of 25% of drugs on the market and is important for metabolism of SSRIs, tricyclic antidepressants, and antipsychotics. CYP2D6 is a highly polymorphic gene and variation in the gene can lead to the following phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM). The phenotype prevalence in Caucasians is 5% to 10% PM, 35% IM, 7% UM; in African Americans and Asians the prevalence is 1% to 3% PM. CYP2D6 poor and intermediate metabolizers may not be able to effectively metabolize certain psychotropic medications, and may experience side effects. CYP2D6 ultrarapid metabolizers may not benefit from certain psychotropic medications.

Mayo Medical Laboratories offers several tests that can be used as aids for predicting an individual’s response to psychotherapeutics. For CYP2D6, order 2D6/83180 Cytochrome P450 2D6 Genotype; it detects the presence of numerous CYP2D6 alleles. Other tests from Mayo Medical Laboratories include the following genotypes: CYP2C19, CYP2C9, CYP1A2, serotonin transporter, serotonin receptors 2A and 2C, and dopamine receptors D3 and D4.

Mayo Medical Laboratories Assays to Predict Response to Psychotropic Medications
•   2D6/83180 Cytochrome P450 2D6 Genotype
•   2C19S/60439 Cytochrome P450 2C19 Genotype by Sequence Analysis
•   2C9S/60528 Cytochrome P450 2C9 Genotype by Sequence Analysis, Blood
•   1A2/89401 Cytochrome P450 1A2 Genotype
•   HTT/83302 Serotonin Transporter Genotype, Blood
•   HTR2/83303 Serotonin Receptor Genotype (HTR2A and HTR2C)
•   DRD3/81776 Dopamine Receptor D3 Genotype
•   DRD4/89096 Dopamine Receptor D4 Genotype (DRD4), Blood


Irinotecan Toxicity Due to UGT1A1 Deficiency

The FDA label warning for irinotecan toxicity  due to UGT1A1 deficiency was issued in July 2005. UGT1A1 is a primary enzyme involved in the metabolism of irinotecan, which is a camptothecin analogue widely used for the treatment of solid tumors. Irinotecan is given as a prodrug that is activated by carboxylesterases to its active form, referred to as SN-38. UGT1A1 inactivates SN-38 via  a conjugation reaction known as glucuronidation. Severe leukopenia/neutropenia or diarrhea can occur during irinotecan treatment and has been linked to UGT1A1 polymorphisms.

Numerous UGT1A1 alleles can lead to deficient UGT1A1 activity. The most common allele in many populations occurs in the promoter region of the gene. The UGT1A1 promoter contains a TA repeat region that may contain 5 to 8 TA repeats. Normal or wild-type activity of UGT1A1 is associated with 6 TA repeats. Deficient UGT1A1 activity occurs with 7 or 8 TA repeats, also known as *28 and *37, respectively. These alleles are associated with irinotecan toxicity and hyperbilirubinemia.

Mayo Medical Laboratories offers 4 tests for UGT1A1 genetic analysis.

Carbamazepine and Abacavir Hypersensitivity and Genetic Variation in the HLA-B Gene

The final group of pharmacogenomic-related applications is hypersensitivity to carbamazepine and abacavir due to genetic variation in the HLA-B gene. These label warnings were issued in December 2007 and July 2008, respectively.

Drug hypersensitivity affects approximately 7% of the general population and can manifest as a variety of nonspecific and often times serious side effects. Almost all drugs can induce hypersensitivity reactions that are typically dose-independent and unpredictable. Human leukocyte antigens (HLA) play a central role in the immune reaction and immune responsiveness. This is the process by which the immune system recognizes an antigen, in this case a drug, as being foreign, or antigenic, and proceeds to mount an immune response. The response is meant to protect, but can lead to clinical symptoms of hypersensitivity. Certain HLA alleles have been associated with hypersensitivity to certain drugs. The HLA genes are located at the major histocompatibility complex (MHC) region on chromosome 6 (6p21.3), which contains about 200 genes, including more than 10 highly polymorphic HLA genes.

Carbamazepine

Carbamazepine is an anticonvulsant, used to treat epilepsy, manic/bipolar disorders, and neuropathic pain. Hypersensitivity to carbamazepine is a leading cause of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). The HLA-B*1502 allele is positively correlated to carbamazepine-associated SJS/TEN, and occurs mainly in individuals of southeast Asian descent. The HLA-B*1502 allele is also associated with hypersensitivity to phenytoin  and fosphenytoin.

Mayo Medical Laboratories offers testing that can be used to assist in predicting a hypersensitivity reaction to carbamazepine, phenytoin, and fosphenytoin. Testing can be done on whole blood: HLA15/89347 HLA-B 1502 Genotype, Carbamazepine Hypersensitivity or saliva: HL15O/60348 HLA-B 1502 Genotype, Carbamazepine Hypersensitivity, Saliva.

Abacavir

Another HLA-B allele, *5701, is associated with hypersensitivity to the HIV drug abacavir. About 5% to 8% of AIDS patients develop a hypersensitivity reaction to abacavir. There is a strong association between HLA-B*5701 and abacavir hypersensitivity in Caucasians. It has been demonstrated that HLA-B*5701 screening can be used for risk stratification of patients. When the HLA-B*5701 allele is present, there is a high risk for a hypersensitivity reaction to abacavir with a positive predictive value of approximately 58%5. When the HLA-B*5701 allele is absent, there is a low risk for hypersensitivity reaction to abacavir with a negative predictive value of approximately 100%.6

Mayo Medical Laboratories testing can be used to assist in predicting a hypersensitivity reaction to abacavir. Testing can be done on whole blood: HLA57/89346 HLA-B 5701 Genotype, Abacavir Hypersensitivity, or salivaHL57O/60347 HLA-B 5701 Genotype, Abacavir Hypersensitivity, Saliva.

Conclusion

Pharmacogenomic tests can help determine the appropriate drug or the appropriate dose of a drug. The goals of pharmacogenomics are to maximize drug efficacy and minimize side effects. There are many different tests available for a variety of clinical applications. Pharmacogenomic testing can identify individual genetic variations to assist clinicians to make more informed prescribing decisions, thus reducing the risk of adverse events and increasing the likelihood of treatment success.

Authored by Linnea M. Baudhuin, PhD

References

  1. Mega JL, Close SL, Wiviott SD, et al: Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009 Jan 22;360(4): 354–362
  2. Levine GN, Bates ER, Blankenship JC, et al: 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary: Title and subTitle BreakA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58(24):2550–2583
  3. Package insert: Coumadin (warfarin sodium). Bristol-Myers Squibb, Princeton, NJ, Rev October 2011. Available at: http://packageinserts.bms.com/pi/pi_coumadin.pdf
  4. Epstein RS, Moyer TP, Aubert RE, et al: Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010 Jun 22;55(25):2804–2812
  5. Martin AM, Nolan D, Gaudieri S, et al: Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA 2004 Mar 23;101(12):4180–4185
  6. Mallal S, Phillips E, Carosi G, et al: HLA-B*5701 screening for hypersensitivity to abacavir.  N Engl J Med 2008 Feb 7;358(6):568–579


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