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The Use of Genetics in Guiding Therapy

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Published: June 2012

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In recent years, the Food and Drug Administration has introduced pharmacogenetic-related drug label warnings and precautions, including black box warnings, on some widely prescribed drugs in an effort to reduce adverse effects. Advances in the study of pharmacogenomics have resulted in development of tests to identify patients who would benefit from different treatment levels or the use of different drugs. Dr. Baudhuin provides an update of pharmacogenetics with a focus on drugs with FDA label warnings and precautions, the related pharmacogenetic tests available, and their use in the clinical setting.

Presenter: Linnea M. Baudhuin, PhD

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Introduction

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Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this program is Dr. Linnea Baudhuin, an Assistant Professor of Laboratory Medicine and Pathology at Mayo Clinic, as well as a consultant in the Divisions of Clinical Biochemistry and Clinical Core Laboratory Services, and the Department of Medical Genetics. Dr. Baudhuin provides an update on the state of pharmacogenetic testing and the clinical application of pharmacogenetic biomarkers. Thank you, Dr. Baudhuin.

Thank you for the introduction and thank you for joining me for this update on The Use of Genetics in Guiding Therapy.

Pharmacogenomics

Pharmacogenomics is a component of individualized medicine. It focuses on how genetic factors influence individual responses to different medications, which may affect drug efficacy, drug side effects, and adverse events related to the therapy.The clinical goals of pharmacogenomics are to minimize adverse drug events and maximize drug efficacy.

PGx Biomarkers in Drug Labels

Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labels may contain information on genomic biomarkers and can describe for example: drug exposure and clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms of drug action and polymorphic drug target and disposition genes.

FDA-Approved Drugs with PGx-Related Label Information

Some examples of FDA-approved drugs with pharmacogenomics-related label information are shown here. You can see that there are a variety of biomarkers, therapeutic areas, and drugs associated with pharmacogenomics-related label information.

For the purposes of the discussion here, we will focus on some of the FDA-approved drugs that have Boxed Warnings or other label Warnings or Precautions related to PGx, as highlighted in blue.

The FDA and PGx-Related Drug Label Updates

The first of these that I would like to discuss is the anti-platelet drug, clopidogrel. In March 2010, the FDA issued a label warning update for response to the drug by CYP2C19 poor metabolizers.

Clopidogrel (Plavix)

Clopidogrel, or Plavix, is a commonly used anti-platelet drug which is administered as an inactive prodrug and metabolized to its active form by CYP or cytochrome P450 enzymes. It is used to reduce atherosclerotic events in patients with acute coronary syndrome and/or following Percutaneous Coronary Intervention or PCI. It is often given as alternative to aspirin or in combination with aspirin which is known as dual antiplatelet therapy. There is a highly variable response to clopidogrel where it is efficacious in some, and not efficacious in others. This can be due to many variables including underdosing and interactions with CYP inhibitors and substrates, as well as genetics.

CYP2C19 and Response to Clopidogrel

As mentioned in the previous slide, clopidogrel is given as a prodrug. It is metabolized to its active form by CYP2C19 and other enzymes. CYP2C19 has several loss of function alleles, but the two alleles that have been studied the most in relation to clopidogrel are the *2 and *3 alleles, for which you can see their ethnic distribution here. These alleles are associated with lower levels of active metabolite of clopidogrel and a marked decrease in platelet responsiveness to clopidogrel (in other words, 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, this landmark study showed a relative 53% increased risk of death from cardiovascular causes, MI, or stroke, and a 3-fold increased risk of stent thrombosis in patients who were taking clopidogrel and had a CYP2C19 loss of function allele, compared to patients taking clopidogrel without CYP2C19 loss of function alleles. Higher risks for cardiovascular events and stent thrombosis have been demonstrated for both heterozygote and homozygote *2 carriers who are given clopidogrel. What these studies and others have demonstrated is that individuals with CYP2C19 loss of function alleles who are taking clopidogrel might not receive benefit from the drug.

CYP2C19 PGx Testing for Clopidogrel

CYP2C19 testing for predicting response to clopidogrel is currently performed clinically. However, the widespread adoption of this testing has not yet occurred and may be due, in part, to the lack of recommendation as per the 2011 guidelines by the American College of Cardiology 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 can be more fully embraced.

Mayo CYP2C19 Test

Mayo Medical Laboratories offers a test that can be ordered as an aid for predicting an individual’s response to clopidogrel. This test is the CYP2C19 sequence genotype, which is a sequencing-based assay that detects the presence of the star alleles listed here as well as any other rare variants that may occur in the regions sequenced. This test may be additionally useful for psychiatry applications, as discussed later.

The FDA and PGx-Related Drug Label Updates

The second PGx application that I would like to discuss is warfarin pharmacogenetics, which has 2 FDA-issued label warnings. The first was issued in August 2007, and was in reference to warfarin sensitivity in CYP2C9 poor metabolizers. The second warfarin label update was issued in January, 2010, and this label included the effect of a second gene, VKORC1, as well as a table with PGx guided dosing ranges for the drug.

Warfarin

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

Warfarin PGx

There are two major genes involved in warfarin PGx. CYP2C9 is one of the enzymes responsible for the metabolism of warfarin. 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 promoter variant at -1639G>A, can lead to warfarin sensitivity or mild warfarin resistance, depending on which combination of alleles are present. The table show here is from the warfarin, or Coumadin, package insert. This table is a genotype-guided dosing table and is based on the combination of CYP2C9 *2 and *3 alleles and VKORC1 promoter polymorphism alleles that may be present in an individual.

Allele Frequencies

The allele frequencies for CYP2C9 *2 and *3 and VKORC1 in different ethnic groups are shown here. It is interesting to point out that the majority of warfarin sensitivity in the Asian population is thought to be due to variability at the VKORC1 promoter.

Medco-Mayo Warfarin Effectiveness Study

A fairly recent study 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. And hospital admissions for thromboembolism or bleeding were 28% less frequent in the genotyped group.

Mayo Test for Warfarin Sensitivity

Mayo Medical Laboratories offers a test that can be used as an aid for predicting an individual’s sensitivity to warfarin. This test is the Warfarin Sensitivity Genotype, which is a sequencing-based assay that detects 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. The CYP2C9 sequence genotype test may be additionally useful for psychiatry applications, as discussed later.

FDA-Approved Drugs with PGx-Related Label Information

The next group of drugs with PGx related label information are drugs used in psychiatric applications, as highlighted here in blue.

Most Psychotropic Medications Are Metabolized by CYPs

Most psychotropic medications are metabolized by CYP’s, 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 listed here.

CYP450 Testing — Psychotherapeutics

The 3 major CYPs for which psychotherapeutic pharmacogenomic testing is available are CYP2C9, CYP2C19, and CYP2D6. Shown here is an incomplete list of psychotherapeutics metabolized by these enzymes.

CYP2D6

CYP2D6 is involved primarily or substantially in the metabolism of 25% of drugs on the market. CYP2D6 is important for metabolism of TCAs, SSRIs, and antipsychotics. CYP2D6 is a highly polymorphic gene and variation in the gene can lead to phenotypes ranging from poor metabolizer or PM to ultrarapid metabolizer or UM. The phenotype prevalence in Caucasians and other ethnic groups is shown here.

Mayo Test for CYP2D6

Mayo Medical Laboratories offers a test that can be used as an aid for predicting an individual’s response to psychotherapeutics. This test is the CYP2D6 Genotype. The CYP2D6 Tamoxifen test is a separate test that can be ordered as an aid in the prediction of an individual’s response to tamoxifen therapy, which is a drug used in the treatment of breast cancer.

Mayo Tests for CYP2D6

The CYP2D6 genotype tests described in the previous slide detect the presence of numerous CYP2D6 alleles as shown in the table.

Additional Mayo Tests for Psychiatric Applications

Additional tests that Mayo Medical Laboratories offers for predicting an individual’s response to psychotropic medications are listed here, and include CYP2C19, CYP2C9, CYP1A2, the Serotonin Transporter, the Serotonin receptors 2A and 2C, and the dopamine receptors D3 and D4. For additional information on these tests, please visit the Mayo Medical Laboratories web page.

The FDA and PGx-Related Drug Label Updates

The next PGx-related application that I will be discussing is irinotecan toxicity due to UGT1A1 deficiency. The FDA label warning for this PGx application was issued in July of 2005.

UGT1A1

UGT1A1 is a primary enzyme involved in the metabolism of irinotecan. Irinotecan is a camptothecin analogue widely used for treatment of solid tumors. Severe, occasionally fatal, leukopenia/neutropenia or diarrhea can occur during irinotecan treatment and has been linked to UGT1A1 polymorphisms.

Irinotecan Metabolism

Irinotecan is given as a prodrug that is activated by carboxylesterases. The active form of the drug is referred to as SN-38. UGT1A1 inactivates SN-38 via a conjugation reaction known as glucuronidation.

UGT1A1 Genetic Variants

Numerous UGT1A1 alleles can lead to deficient UGT1A1 activity. The most common allele that occurs in many populations occurs in the promoter region of the gene. The UGT1A1 promoter contains a TA repeat region that can have 5-8 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, and these alleles are also associated with hyperbilirubinemia and irinotecan toxicity.

Mayo Tests for UGT1A1

Mayo Medical Laboratories offers 3 tests involving UGT1A1 genetic analysis. The first, UGT1A1 TA Repeat Genotype, analyzes the promoter specifically for the TA repeat region. The second test, UGT1A1 gene sequence, irinotecan, is a sequence analysis of the entire UGT1A1 gene, including the promoter region. Both of these tests can be used to aid in determining an individual’s potential hypersensitivity response to irinotecan. The third test, UGT1A1 gene sequence, hyperbilirubinemia is a sequence analysis of the entire UGT1A1 gene, including the promoter region. This test is useful in the evaluation of individuals with unconjugated hyperbilirubinemia to determine if there is a genetic basis for their high bilirubin levels. A fourth UGT1A1 test is also available but not listed here. This test is the UGT1A1 Known Mutation test and is mainly used for patients who would like to be tested for a known familial UGT1A1 mutation. More information about all of these tests can be found on the Mayo Medical Laboratories website.

The FDA and PGx-Related Drug Label Updates

The final group of PGx-related applications that I will be discussing is related to hypersensitivity to carbamazepine and abacavir due to genetic variation in the HLA-B gene. These label warnings were issued in Dec, 2007 and July 2008 respectively.

Human Leukocyte Antigens and Drug Hypersensitivity

Drug hypersensitivity affects approximately 7% of the general population and can manifest as a variety of non-specific and oftentimes serious side-effects. Almost all drugs can induce hypersensitivity reactions which are typically dose-independent and unpredictable. Human leukocyte antigens (or HLA) play a central role in the immune reaction by initiating an immune response by presenting antigen to the T-cell receptor. 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.

HLA-B*1502

The HLA-B*1502 allele is associated with hypersensitivity to carbamazepine, phenytoin, and fosphenytoin. 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.

Mayo Test for HLA-B*1502

Mayo Medical Laboratories offers a test that can be used as an aid for predicting a hypersensitivity reaction to carbamazepine, phenytoin, and fosphenytoin. This test is the HLA-B*1502 Genotype.

HLA-B*5701

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 HLAB*5701 allele is present, there is a high-risk for a hypersensitivity reaction to abacavir with a positive predictive value of approximately 58%. When the HLAB*5701 allele is absent, there is a low-risk for hypersensitivity reaction to abacavir with a negative predictive value of approximately 100%..

Mayo Test for HLA-B*5701

Mayo Medical Laboratories offers a test that can be used as an aid for predicting a hypersensitivity reaction to abacavir. This test is the HLA-B*5701 Genotype.

Summary

In summary, pharmacogenetic tests can help to determine the appropriate drug and, sometimes, the appropriate dose of a drug. The goals of PGx are to maximize drug efficacy and minimize side-effects. There are many different PGx tests available for a variety of clinical applications.

Thank you for your attention to this Hot Topic presentation.


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