Pharmacogenomics in Women's Health

Release Date: September 1, 2013

Expiration Date: September 30, 2015

FACULTY:

David F. Kisor, BS, PharmD
Professor of Pharmacokinetics

Kelly R. Kroustos, PharmD
Assistant Professor of Pharmacy Practice
Ohio Northern University
Raabe College of Pharmacy
Ada, Ohio

FACULTY DISCLOSURE STATEMENTS:

Drs. Kisor and Kroustos have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
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UAN: 0430-0000-13-023-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists regarding pharmacogenomics and its application to drug therapy in diseases that have a significant prevalence in women.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Define and differentiate pharmacogenomics and pharmacogenetics.
  2. Describe how genetic variation is related to pharmacokinetics and pharmacodynamics.
  3. Identify prevalent diseases in women for which a drug-gene interaction would be of interest.
  4. Specify drug-gene interactions related to drug selection and dosing.
  5. Describe pharmacogenetic test results for the examples provided relative to drug selection and dosing.


ABSTRACT: Pharmacogenomics, relating genetics to pharmacokinetics and pharmacodynamics, is a rapidly expanding field that can be applied to drug and dosage selection. Pharmacogenomic biomarkers (e.g., proteins) used for drug selection and dosage alteration are found in the package labeling for many drugs. The use of these biomarkers can lead to improved drug efficacy while decreasing or avoiding the risk of adverse drug reactions. Examples of the application of pharmacogenomic biomarkers in diseases prevalent in women are presented. Pharmacists will be viewed as drug-gene interaction experts and must understand the application of pharmacogenomic information.

A patient's response to a given drug can be influenced by diet, environmental factors, concomitant medication use, and pathophysiology. Underlying these variables is the individual's genetic constitution, which can introduce "baseline variability" depending on the sequence of nucleotides, the triphosphates of adenine (A), cytosine (C), guanine (G), and thymine (T) that constitute deoxyribonucleic acid (DNA). Approximately 25,000 genes are found in the entirety of DNA that is the human genome.1 The genes code for various proteins (sequences of amino acids), including drug receptors, drug transporters, and drug metabolizing enzymes, which are all considered "drug targets" (FIGURE 1).1


table3

Relating genetics to drug response is the basis of pharmacogenomics (PGx), which can be defined as the study of many genes, in some cases the entire genome, involved in response to a drug.1,2 This term is broader in scope as compared with pharmacogenetics, which is defined as the study of a single gene involved in response to a drug.1,2 The term pharmacogenomics and the accompanying PGx abbreviation will be used throughout this article to encompass pharmacogenetics as well.

The smallest of genetic changes can result in altered function of drug targets. Single nucleotide polymorphisms (SNPs; pronounced "snips") are the most common DNA alterations that introduce genetic variation. A substitution, insertion, or deletion of a single nucleotide can render a drug target deficient or nonfunctional, and some SNPs are related to increased drug-target activity (FIGURE 2).1 A SNP refers to a change in a nucleotide base at a specific location on a gene. As we receive genetic information from each parent, an individual has two sets of genetic information (23 pairs of chromosomes), and the nucleotide in the same location on each gene on a given chromosome represents the individual's genotype. For instance, at a specific locus on a given gene an individual may have an A and at the same locus on the other copy of the gene, the individual may have a G; thus, the genotype for that individual for that specific locus would be AG. The variation in a gene due to a SNP can be represented by the "star (*)" nomenclature. For instance, typically the most common form of a gene is designated as the *1 form or wild-type, whereas a variant form of the gene (allele) would have another designation, such as *2, *10, *17, or *41.1 The star nomenclature has been commonly used when designating CYP450 metabolizing enzyme gene variants. Numerous examples are presented below; however, the star nomenclature is not used in all cases.


table3

SNPs can influence drug dosing in many ways. For example, a SNP that results in decreased production of a target drug receptor can lead to an individual being overly "sensitive" to the standard dose of a given drug. In this case, a decreased dose would be required. A SNP may result in decreased activity of a metabolizing enzyme, resulting in a decreased drug clearance necessitating the need for a decreased maintenance dose of active drug or, conversely, an increased dose of a prodrug, or potentially the use of an alternative drug. A SNP resulting in decreased metabolism also prolongs the half-life of a given substrate active drug, which can lead to drug accumulation and increased risk of toxicity. Here, a need for a longer dosing interval may be required. In the case of drug transporters, a SNP can alter the function of a given transporter, leading to altered drug distribution that can influence drug response, e.g., inefficacy where there is decreased distribution of a drug into the target tissue or cells. It should be recognized that SNPs can alter all aspects of pharmaco- kinetics (e.g., absorption, distribution, metabolism, excretion) as well as pharmacodynamics.

Currently, more than 110 drugs across the spectrum of therapeutic areas contain PGx information in the package labeling, which relates genetic biomarkers (genes coding for drug targets) and other biomarkers to pharmacokinetics and/or pharmacodynamics.3 The biomarkers can be classified as being pharmacokinetic (e.g., transporters) and enzymes or pharmacodynamic (e.g., receptors).1

With respect to women, pathologic conditions with an increased prevalence in women (e.g., breast cancer) can be considered relative to PGx. Here, we include discussion of examples of the PGx of drugs used in women for various therapeutic reasons that have biomarker information in the package labeling (TABLES 1, 2, and 3).3 Examples are provided for a number of therapeutic areas; however, the reader is encouraged to view the entire Table of Pharmacogenomic Biomarkers in Drug Labels (TPB).3 This FDA table should be referred to periodically, as it is continuously updated.


table1


table2


table3

CARDIOVASCULAR DISEASE

Cardiovascular disease (CVD) is the leading cause of death in women, with more than 400,000 deaths due to all forms of CVD annually.4 This exceeds deaths annually in women due to all forms of cancer by more than 100,000.4 Approximately 6.6 million women have coronary heart disease, with just under 40% having had a myocardial infarction (MI).4 Primary prevention strategies to reduce the risk of MI or stroke in patients with either CVD or CVD risk factors include treatment with HMG-CoA reductase inhibitors (statins), with related atherothrombotic events being prevented with antiplatelet therapy.

Currently, the TPB lists eight CVD drugs with PGx information in the package labeling.3 Additionally, three drugs used for related cardiovascular indications are listed under the therapeutic areas of hematology, metabolic, and endocrinology (TABLE 1).3

Biomarker: CYP2C19 / Type: Pharmacokinetic
Approximately 30% to 50% of individuals carry the most common CYP2C19 gene, being *1/*1 individuals considered "normal" or extensive metabolizers (EMs).5 There are in excess of 25 known variant forms of the CYP2C19 gene.5 The most common variant form of the gene is the *2 form (CYP2C19*2), where a synonymous SNP (i.e., A replaces G) resulting in the same amino acid (proline) being coded for, still results in a "loss-of-function" CYP2C19 drug-metabolizing enzyme. Here, the adenine-replacing guanine causes a "splicing defect" where needed genetic material is removed.1 An individual with one normal (wild-type; *1) copy of the gene and one *2 variant (*1/*2) is considered an intermediate metabolizer (IM), and a *2/*2 individual is termed a poor metabolizer (PM). There are other loss-of-function variant forms of the CYP2C19 gene (*3-*8); however, they are seen at a lower frequency than the *2 form.

A "gain-of-function" form of the CYP2C19 gene has been identified. The *17 form would be expected to result in increased CYP2C19 drug substrate metabolism and efficient conversion of a prodrug to its active compound. An individual with the *1 form from one parent and the *17 form from the other parent would be considered an ultrarapid metabolizer (UM), as would *17/*17 individuals.5 An individual with a loss-of-function form (*2) and a gain-of-function form (*17) has the metabolic capacity of an IM. Here, the gain-of-function variant does not "make up" for the loss-of-function variant.

The consequences of having one or two copies of the loss-of-function variant include a decreased clearance, higher concentrations, and longer half-life for drugs that are metabolized by CYP2C19. This results in a greater drug exposure, with an increased risk of toxicity. Additionally, there would be a decrease in the formation of active compound from a prodrug for drugs activated by CYP2C19, potentially resulting in inefficacy.

Clopidogrel: Annually in the United States, more than one million coronary artery stents are placed to maintain vessel patency in an effort to prevent CVD complications, including death. The standard of care for patients with stent placement, to prevent thrombosis, includes the use of dual antiplatelet therapy with aspirin and an antiplatelet agent such as the prodrug clopidogrel.6,7

Clopidogrel in the context of preventing stent thrombosis provides an example of indication-specific use of pharmacogenetic testing of CYP2C19.8 Individuals with a stent (bare metal or drug eluting), who are CYP2C19 IMs (e.g., *1/*2) or PMs (e.g., *2/*2), should receive antiplatelet therapy with a drug other than clopidogrel (e.g., prasugrel or ticagrelor).5 This is based on decreased bioactivation of clopidogrel, which results in patients being at increased risk of cardiovascular events.

Biomarker: LDLR / Type: Pharmacodynamic
Approximately 70% of plasma low-density lipoprotein (LDL) is moved by LDL receptors (LDLRs) into the liver as an uptake mechanism, resulting in catabolism of LDL. There are over 800 LDLR gene variants, which can result in various degrees of altered hepatic uptake of LDL.9 The activity of the LDLR can be decreased by 75% to 100%, resulting in increased LDL concentrations in the plasma.

Atorvastatin: This statin is indicated for the treatment of hypercholesterolemia.10 Beyond decreasing the synthesis of cholesterol, atorvastatin has also been shown to increase the LDLRs on hepatocytes, which increases uptake and catabolism of LDL. With a variant LDLR gene, atorvastatin can upregulate deficient LDLRs.9,10

Biomarkers: CYP2C9, VKORC1 / Types: Pharmacokinetic, Pharmacodynamic
A number of CYP2C9 SNPs result in deficient CYP2C9 enzyme activity. The *2 and *3 variant forms are related to decreased metabolism, resulting in decreased drug clearance and a longer half-life.1,11 The *2 form is found in 13% and 3% of white and black individuals, respectively, whereas the *3 form is found in 7%, 4%, and 2% of white, Asian, and black individuals, respectively.11 Other variant forms (e.g., *5, *6, *8, *11) of the CYP2C9 gene are present at different frequencies in various populations and result in decreased enzyme activity. Individuals with a CYP2C9 variant resulting in decreased enzyme activity require lower doses of substrate drugs to elicit therapeutic responses. Administration of "normal" doses of CYP2C9 substrate drugs to individuals with deficient enzymes can result in increased risk of toxicity.

Vitamin K 2,3-epoxide is converted to its active form by vitamin K epoxide reductase complex subunit 1 (VKORC1).11 Vitamin K, in its active form, is used in the process of carboxylating glutamic acid residues in certain clotting factors, including II, VII, IX, and X. VKORC1 is responsible for recycling vitamin K and is involved in the production of active clotting factors.

Haplotypes are regions of DNA with multiple SNPs that are inherited together. With respect to the VKORC1 gene, the *2 haplotype or haplotype A results in decreased production of the enzyme.1 Of the four important haplotypes, the *1 form is the common form imparting normal VKORC1 activity. The variant *2 haplotype is most common, being observed in 40% of whites and 90% of Asians. This form of the haplotype is observed in <15% of African Americans.1,11 While pharmacogenetic testing relative to VKORC1 is not currently recommended, pharmacists should recognize the various populations that have a higher frequency of the *2 variant, understanding that individuals from these populations may be more sensitive to warfarin.

Warfarin: The more potent S enantiomer of warfarin is metabolized to 7-hydroxywarfarin by CYP2C9. Individuals who are heterozygous, with one wild-type (normal) form of the CYP2C9 gene and one variant form (e.g., *1/*2) or individuals with two variant forms (e.g., *2/*3) have decreased warfarin dosage requirements due to decreased drug metabolism (clearance).11 Warfarin works by inhibiting VKORC1, which results in decreased active vitamin K and decreased vitamin K–dependent clotting factors. Individuals with a variant VKORC1 haplotype (e.g., *2 or A) require less warfarin due to decreased amounts of VKORC1. Individuals with variant CYP2C9 and VKORC1 genes require the lowest warfarin doses. In 2010, the FDA included a genetic-based maintenance-dosing chart in the warfarin package labeling.11

While altered warfarin pharmacokinetics and pharmacodynamics have been noted in certain individuals with variant genes, pharmacogenetic testing is not currently recommended. Data from a prospective study evaluating the usefulness of CYP2C9 and VKORC1 testing in warfarin dosing will be reported in the near future and may result in a change in the current recommendation.11

ONCOLOGY: BREAST CANCER

Approximately one out of eight women will be diagnosed with breast cancer at some point during their lifetime, with the highest incidence occurring between the ages of 55 to 64 years.12,13 Risk factors for the development of breast cancer include female gender, advancing age, family history of breast cancer at a young age, early menarche (12 years of age or younger), menopause after 55 years of age, 30 years of age or older for first live child birth, prolonged hormone replacement therapy, previous exposure to therapeutic chest wall radiation, benign proliferative breast disease, increased mammographic density, and genetic mutations such as breast cancer genes 1 (BRCA1) and 2 (BRCA2).12,13 The presence of these genes increases a woman's risk of developing breast cancer and is currently estimated to account for approximately 10% of all breast cancers.13 Except for female gender and advancing age, these risk factors account for only a minority of breast cancers. Cancer guidelines offer clinicians recommended screening for genetic/familial assessment and corresponding breast cancer risk reduction strategies.12

The American Joint Committee on Cancer staging manual recommends collecting prognostic factors or biomarkers including: human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). These prognostic factors do not influence the staging of the disease.12 However, the presence of these specific prognostic factors or biomarkers can help predict clinical responses to therapy and further assist clinicians in selecting appropriate chemotherapy and endocrine therapy.12

ER tumor status should be reported for all ductal carcinoma in situ (DCIS) and ER, PR, and HER2 tumor status. In addition, HER2 tumor status should be reported for all invasive breast cancers and retested on sites of breast cancer recurrence if previously unknown or negative.

Patients diagnosed with invasive breast cancer who are either ER- or PR-positive should be considered candidates for adjuvant endocrine therapy regardless of the patient's age, lymph node status, or whether chemotherapy is to be administered.12 Typically, if chemotherapy is indicated, it is administered initially followed by treatment with endocrine therapy, such as tamoxifen in the pre- or postmenopausal settings. Other endocrine therapies include anastrozole, letrozole, or exemestane as aromatase inhibitors used most commonly in postmenopausal women.

HER2 provides predictive information guiding the selection of initial targeted therapy in combination with other chemotherapy. Additionally, HER2 also provides predictive information in the selection of adjuvant/ neoadjuvant chemotherapy for patients with recurrent or metastatic breast cancer with anthracycline-based adjuvant chemotherapy providing superior outcomes in patients with HER2-positive tumors. When excess amounts of the HER2 are detected, then medications that target HER2 proteins, such as trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are indicated in conjunction with adjuvant/neoadjuvant chemotherapy (TABLE 2).

Biomarker: HER2 (HER2/neu; ERBB2) / Type: Pharmacodynamic
HER2 is a protein receptor coded by the HER2 gene. The interaction of human epidermal growth factor and the HER2 receptor results in increased cell growth. In some breast cancers, a gene variant (mutation) results in overexpression of HER2, allowing for increased interaction with human epidermal growth factor, leading to uncontrolled cell growth.14 The overexpression of HER2 is termed HER2-positive breast cancer and relates to a more aggressive disease.

Lapatinib: Lapatinib is indicated for treatment of HER2-positive advanced or metastatic breast cancer in patients who had previously been treated with an anthracycline, a taxane, and trastuzumab. Lapatinib is used concurrently with capecitabine.15

Lapatinib is a tyrosine kinase inhibitor, which intracellularly disrupts the HER2 receptors and inhibits tumor growth. Therefore, lapatinib is indicated when a patient is HER2-positive, indicating a more aggressive form of breast cancer.

Pertuzumab: Pertuzumab is indicated in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic breast cancer in patients who have yet to be treated with anti-HER2 therapy or chemotherapy.16

Pertuzumab is a monoclonal antibody (humanized) that targets the HER2 receptor. The interaction with the extracellular (cell surface) portion of the HER2 receptor results in blocking of intracellular chemical signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K).16 The interruption of these signaling pathways results in apoptosis.

Trastuzumab: Trastuzumab is used concomitantly with paclitaxel as first-line treatment of HER2-positive metastatic breast cancer.17 It is also indicated in combination with other agents in the adjuvant setting.18

Trastuzumab is a humanized monoclonal antibody that targets the extracellular portion (domain) of HER2. The drug induces antibody-dependent cellular cytotoxicity, where the immune system utilizes natural killer cells, among others, resulting in target tumor cell lysis.18

Biomarker: ER / Type: Pharmacodynamic
ERs are proteins expressed on breast cancer cells that can respond to estrogens, resulting in cancer cell growth.19 Treatment approaches to ER-positive breast cancer include blocking the hormone receptors and/or decreasing hormones in the body. Breast cancers expressing hormone receptors may make treatment amenable to certain types of therapy.

Exemestane: Exemestane is currently indicated to complete 5 consecutive years of adjuvant treatment using hormonal therapy in postmenopausal women who have received at least 2 years of tamoxifen for ER-positive breast cancer.20 The drug can also be used in advanced breast cancer in postmenopausal women, where tamoxifen has failed.20

In postmenopausal women, androstenedione and testosterone, from adrenal and ovarian sources, are converted by aromatase to estrone and estradiol (estrogens) in peripheral tissues.20 These estrogens can interact with estrogen receptors to promote breast cancer cell growth. Exemestane is an inhibitor of aromatase and leads to the depletion of estrogen, resulting in effective treatment in ER-positive breast cancer.20

Fulvestrant: Fulvestrant is indicated for use in post- menopausal women with ER-positive metastatic breast cancer in which the disease progressed subsequent to antiestrogen treatment.21 As an estrogen receptor antagonist, fulvestrant binds to ERs, competitively inhibiting estrogen (e.g., estradiol) stimulation of cancer growth. The number of ERs decrease in fulvestrant- treated patients as the drug results in downregulation of the protein.21

Tamoxifen: Tamoxifen has multiple indications in treatment of breast cancer, including metastatic disease in women and men. Recent data support adjuvant therapy with tamoxifen in ER-positive disease for 10 years as opposed to the current standard of 5 years. There were significantly fewer recurrences of disease with the longer adjuvant treatment.22 Tamoxifen is metabolized to two important active metabolites by CYP2D6. In CYP2D6, PM's tamoxifen efficacy may be reduced, as there is decreased conversion to the important active metabolites. This drug-gene interaction is not unlike a drug-drug interaction, such as noted between the selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, paroxetine), which are used to treat hot flashes, and tamoxifen.23 As an example, fluoxetine inhibition of CYP2D6 can lead to reduced efficacy of tamoxifen by decreasing the formation of the active metabolites.

FIBROMYALGIA

Fibromyalgia is considered an arthritis-related condition characterized by widespread pain, diffuse tenderness, and generalized fatigue, with negative impact on activities of daily living and overall quality of life. It is estimated that fibromyalgia impacts 5 million Americans, with 80% to 90% consisting of women 18 years of age or older.24 The most common nonpharmacologic interventions for the management of fibromyalgia symptoms include moderate-intensity aerobic exercise, cognitive behavioral therapy, and mild strength training.

Tricyclic antidepressants, such as amitriptyline, nortriptyline, and desipramine, have demonstrated efficacy in the management of fibromyalgia-related pain, fatigue, and sleep disturbances.25 Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs provided benefit for pain, fatigue, and overall improvement in quality of life as measured by the Fibromyalgia Impact Questionnaire.25

The muscle relaxer cyclobenzaprine has a chemical structure similar to tricyclic antidepressants and was reported to show sleep improvements with conservative improvement in pain, stiffness, and fatigue.26 Carisoprodol is a centrally acting muscle relaxant that may also be of short-term benefit in relieving discomfort related to painful musculoskeletal conditions in adults. However, side effects can severely limit its use.27 Opioids, such as codeine or morphine, can be used for severe muscle pain; however, there is a lack of evidence demonstrating benefits that outweigh the risks of long-term opioid use (TABLE 3).28

Biomarker: CYP2C19 / Type: Pharmacokinetic
Carisoprodol: Carisoprodol is a muscle relaxant that works in the central nervous system. The drug is metabolized to meprobamate by CYP2C19. Both carisoprodol and meprobamate are known to cause sedation, with 10% to 20% of patients taking carisoprodol experiencing sedation, as compared to less than 10% patients receiving placebo.27 CYP2C19 IMs and PMs are at increased risk of sedation when compared to EMs. PMs, in particular, are at increased risk of sedation with exposure to carisoprodol being four times of that seen in EMs.

Biomarker: CYP2D6 / Type: Pharmacokinetic
There are more than 80 variant forms (alleles) of the CYP2D6 gene that result in the variance seen in the activity of the CYP2D6 enzymes across individuals.29 Five percent to 10% of whites are PMs, with a much smaller percentage of Asians being so (1%).29 The most common loss-of- function alleles are the *3 through *6 forms.29 Additionally, there are "reduced-function" forms such as the *17 and *10 forms, found most predominantly in African Americans and Asians, respectively. The loss-of-function and reduced-function forms are related to decreased drug metabolism, resulting in a lower clearance and higher exposure to CYP2D6 substrate drugs. Additionally, there are a number of cases where multiple copies of a CYP2D6 gene are present, including *1xN, and *2xN. Here, two copies of a form of the CYP2D6 gene, such as the *2 form, would be referred to as duplication, whereas the presence of more than two copies of the *2 form would be referred to as multiplication. Individuals with multiple copies of functional CYP2D6 genes are considered UMs and constitute approximately 1% to 2% of individuals. EMs represent approximately 77% to 92% of the population, whereas about 2% to 11% and 5% to 10% of individuals are IMs and PMs, respectively.29

Tricyclic Antidepressants (Amitriptyline): The clearance of amitriptyline is lower and the half-life is longer in patients who are CYP2D6 PMs, such as those with a *4/*4 genotype.30,31 These individuals are at increased risk for toxicity due to the greater exposure to the drug, i.e., higher concentrations and AUC. As clearance is a determinant of the maintenance dose, individuals who are CYP2D6 PMs would require a lower amitriptyline dose to achieve therapeutic concentrations.

Desipramine: Metabolic variation related to CYP2D6 (e.g., EM vs. PM) can be responsible for the wide variation seen in the concentrations of desipramine. Individuals who are PMs have been noted to have the highest desipramine concentrations and risk of adverse effects.31 As seen with other drugs, the pharmacokinetics of desipramine are different in PMs versus other metabolic phenotypes. Following desipramine dosing, the AUC of the active drug was three times higher in PMs as compared to EMs.31

Doxepin: Like all CYP2D6 drug substrates, inhibition of metabolism by CYP2D6 inhibitors can result in a decreased clearance, leading to higher drug concentrations. The metabolic phenotype of a given individual will influence the magnitude of the interaction.31 For instance, an individual who is a PM will not experience as great of a drug-interaction effect as will the EM individual. This is because as a PM, the function of the enzyme is already diminished and the inhibitor will not further diminish the CYP2D6 enzyme activity. The concentrations of doxepin in a PM were noted to be 16 to 80 times higher than typical therapeutic concentrations, resulting in death due to toxicity of the tricyclic antidepressant. The potential exists for CYP2D6 inhibition converting an EM into a PM, thus increasing the risk of adverse events from doxepin use. Currently, unless a patient has been specifically tested relative to CYP2D6, their metabolizing phenotype will not be known. This identifies the need for preemptive pharmacogenetic testing (where an individual's DNA is sequenced in its entirety). The data can then be stored in a secure database, available for query prior to dosing.32,33 Regardless, as in all drug therapies, the patients must be closely monitored for potential adverse events.

Imipramine: This tricyclic antidepressant is metabolized by CYP2D6 to its hydroxy-metabolite. Additionally, the drug is metabolized by other CYP450 enzymes (2C19, 1A2, 3A4) to desipramine, which also has clinical efficacy. CYP2D6 PMs require doses of 20 mg/day to 25 mg/day, as compared to 50 mg/day to 350 mg/day in EMs, to produce similar combined (imipramine + desipramine) concentrations of approximately 300 to 500 µM.31 Again, inhibitors of CYP2D6 can result in decreased metabolism (clearance) of imipramine, leading to increased concentrations. Here, the magnitude of the interaction would be influenced by the metabolic status of the individual, with, as an example, EMs experiencing a greater interaction than PMs. Downward dosage correction in PMs conceivably would help prevent potential adverse drug reactions.

Nortriptyline: Like imipramine, nortriptyline is metabolized by CYP2D6 to its hydroxy-metabolite, among others. This metabolite has 50% of the potency of nortriptyline. Genetic variation in CYP2D6 can result in decreased metabolism of nortriptyline (IM, PM) or increased metabolism (UM) with increased formation of the hydroxy- metabolite. The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends not using nortriptyline (or amitriptyline) in UMs due to the potential for lack of efficacy.34 It should be noted that CPIC guidelines are in reference to preemptive genetic testing. Patients not responding to or experiencing adverse events from nortriptyline (or other tricyclics) may potentially be explained by their metabolism phenotype.

SSRIs (Citalopram): Citalopram is primarily metabolized by CYP2C19 and CYP3A4. In CYP2C19 PMs, the citalopram maximum concentration (Cmax) and AUC were increased 68% and 104%, respectively.35 Cardiac electrophysiology was shown to be altered as a result of the increased Cmax and AUC, where the QT interval was prolonged. QT prolongation can put an individual at risk for life-threatening arrhythmias, including torsades de pointes.35 PMs should be limited to a maximum daily dose of 20 mg.

Fluoxetine: Beyond being a drug substrate for CYP2D6, fluoxetine is a potent inhibitor of this enzyme. While an individual's genotype may indicate that he or she is an EM, use of fluoxetine in this type of person can result in the individual being a PM. In the presence of fluoxetine, it would be prudent to start with lower doses of drugs metabolized by CYP2D6.36 Although not required, the FDA recommends genetic testing prior to treatment with fluoxetine.

Paroxetine: Paroxetine, like fluoxetine, is an SSRI and a substrate for and inhibitor of CYP2D6; however, the pharmacokinetics of paroxetine have not been extensively studied in CYP2D6 PMs.37 Paroxetine has been shown to display a disproportionate increase in concentration, with an increase in dose (i.e., nonlinear pharmacokinetics). With increasing doses, a lower capacity to metabolize paroxetine could further influence the nonlinear kinetics and confound the drug's use.

SNRIs (Venlafaxine): Venlafaxine is metabolized to its equipotent O-desmethyl metabolite by CYP2D6. Less O-desmethylvenlafaxine (ODV) is formed in CYP2D6 PMs as compared to EMs.38 However, the equipotency of venlafaxine and ODV results in similar clinical response, regardless of metabolizer status. CYP2D6 inhibitors can render an individual as a PM; however, the consequences of this are questionable in the face of equipotent parent and metabolite compounds.

Analgesics (Codeine): Approximately 5% to 10% of a codeine dose is converted (O-demethylated) by CYP2D6 to morphine. UMs are at increased risk of opioid toxicity due to excessive conversion of codeine to morphine.39 Additionally, morphine toxicity and death have been observed in infants who breastfed from mothers who are UMs.39 Conversely, CYP2D6 PMs may not benefit from the analgesic properties of morphine, as little codeine will be converted to the therapeutic agent.39 Codeine should not be used in UMs or PMs.

Tramadol: Tramadol is converted via CYP2D6 to its M1 metabolite (O-desmethyltramadol), and both compounds have analgesic activity.40 In fact, the M1 metabolite has a higher affinity for the muopioid receptor as compared to the parent compound. In a PM, there is less conversion of tramadol to the M1 metabolite. This would result in decreased formation of the higher affinity compound with the potential for decreased response to tramadol. In fact, it has been shown that UMs, EMs, and IMs had lower nonresponse rates than PMs receiving tramadol.40

A study of CYP2D6 showed a 4-fold greater non-response rate to tramadol in CYP2D6 PMs as compared with IMs, EMs, and UMs, likely due to the decreased formation of the M1 metabolite.40 In patients with the CYP2D6*4 genotype, there was a lower rating of pain with tramadol administration.40 There was no relationship between the CYP2D6*4 genotype and adverse effects of tramadol therapy, however.40 Although genotyping a patient relative to CYP2D6 may potentially be useful in identifying patients who may or may not respond to tramadol, it is not currently a standard of care in pain management.

CONCLUSION

Drug therapy for treatment and supportive care of the diseases/conditions discussed above includes the use of compounds with PGx information in the package labeling. In addition to the TPB, many print and digital PGx resources are available, including the Pharmacogenomics Knowledge Base (PharmGKB) and the CPIC dosing guidelines. As drug experts, other health care professionals will look to pharmacists to guide them in the use of PGx testing and the interpretation and application of pharmacogenetic test results. PGx is a fast-changing, ever-expanding field and pharmacists must take the lead in applying this information to optimize drug therapy for our patients.

REFERENCES

  1. Kisor DF, Kane MD, Talbot JN, Sprague JE. Pharmacogenetics, Kinetics, and Dynamics for Personalized Medicine. Burlington, MA: Jones & Bartlett Learning; 2013:19.
  2. E15 definitions for genomic biomarkers, pharmacogenomics, pharmaco-genetics, genomic data and sample coding categories. FDA Regulatory Information. www.fda.gov/RegulatoryInformation/Guidances/ucm129286.htm. Accessed March 27, 2013.
  3. Table of pharmacogenomic biomarkers in drug labels. FDA. www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm. Accessed April 18, 2013.
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