Pharmacogenomics: An Update Lead author: Beth A. Lesher, Pharm.D., BCPS

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1 Detail-Document # This Detail-Document accompanies the related article published in PHARMACIST S LETTER / PRESCRIBER S LETTER July 2005 ~ Volume 21 ~ Number Pharmacogenomics: An Update Lead author: Beth A. Lesher, Pharm.D., BCPS To view our chart of Cytochrome P450 Drug Interactions, please see Detail-Document # Background Two terms, pharmacogenomics and pharmacogenetics, are being used with increased frequency in the medical literature. Pharmacogenomics is the study of how a person s genetic makeup affects drug behavior; pharmacogenetics is the study of how inherited differences affect drug metabolism and response. 1 In most cases, the distinction between these two terms is considered minor and they are currently used interchangeably. For the remainder of this document, the term pharmacogenomics will be used. Traditionally, drugs are prescribed using a one-size fits all approach. In the future, more drugs may be prescribed based on a patient s race or genetic profile. For example, an FDA advisory panel recently recommended that BiDil, (isosorbide dinitrate/hydralazine), be approved for treatment of heart failure in African Americans. But experts point out, not everyone of a particular race will respond to a drug the same way. Pharmacogenomics may enable drugs to be tailormade for individuals based on their genetic makeup. Anticipated benefits of pharmacogenomics include the creation of more powerful medicines targeted to specific diseases; the prescribing of better, safer drugs from the onset of therapy; the determination of appropriate drug doses at the onset of therapy; and the administration of better vaccines. 2 Ultimately, it is hoped that through the use of pharmacogenomics, healthcare care costs can be decreased by decreasing the incidence of adverse drug reactions and the time required for a patient to find an effective therapy, and by improving the drug trial and approval process. there are small differences in the genetic makeup of humans that can affect the way a person responds to a drug. A DNA sequencing variation that occurs with a frequency of at least 1% is known as a genetic polymorphism. 3 Currently, single nucleotide polymorphisms (SNPs) are the most common polymorphisms identified that affect drug response. However, as the field of pharmacogenomics grows, it is anticipated that differences in drug response caused by multiple genes will be more common than those caused by SNPs. 4 Genes appear to affect drug response through pharmacokinetic and pharmacodynamic interactions, and through disease pathways. 5 The practical implications of each of these mechanisms will be discussed below. A table highlighting currently known, clinically important genetic polymorphisms that influence drug response is included at the end of this document. Pharmacokinetic Interactions To date, several genetic polymorphisms that affect a drug s pharmacokinetics through changes in enzyme systems and transporter proteins are identified. Currently, several tests are, or will be, available through various companies such as Genelex ( and Tm Bioscience ( to determine a patient s ability to metabolize drugs. Recently, the FDA approved the Roche AmpliChip CYP450 Test. This test can determine a patient s ability to metabolize drugs through the cytochrome (CYP) 450 2D6 and 2C19 enzyme systems in as little as eight hours. This testing device is currently available in Europe and costs approximately $520 per test. 6 More than 1% of the human population is believed to have a genetic polymorphism that affects the CYP2D6 or CYP2C19 enzyme systems. These patients may either eliminate How Can Gene Variations Affect Drug Response? In general, the genetic makeup of all humans, regardless of race and sex, is similar. However,

2 drugs metabolized through the CYP2D6 or CYP2C19 enzyme systems too quickly (ultrarapid metabolizers), too slowly (intermediate metabolizers), or not at all (poor metabolizers). In general, patients who are ultra-rapid metabolizers may not exhibit a drug response; patients who are intermediate or poor metabolizers may have an adverse effect. An exception to this rule occurs however, when a prodrug is administered. If a drug must be metabolized to an active form, ultrarapid metabolizers can experience an adverse effect and intermediate or poor metabolizers may not exhibit an effect. A clinically relevant example of this exception is the administration of codeine. Codeine is a prodrug that must be metabolized to morphine, the active drug form. Patients who are intermediate or poor CYP2D6 metabolizers may not experience any pain relief following codeine administration whereas those who are ultra-rapid CYP2D6 metabolizers may experience adverse effects. Currently, more than 70 commonly prescribed drugs are metabolized through the CYP2D6 or CYP2C19 enzyme systems including many cardiovascular, antidepressant, and antipsychotic agents. In theory, all patients who have a genetic polymorphism that affects either the CYP2D6 or CYP2C19 enzyme systems could experience an unanticipated effect when administered one of these drugs. In reality however, unanticipated effects occur most commonly when prescribing drugs with steep dose response curves or narrow therapeutic windows. Examples of drugs where genetic polymorphisms may be clinically relevant are listed in the table below. Thiopurine metabolism is another example of a genetic polymorphism that causes a pharmacokinetic interaction that is currently monitored clinically. Genetic polymorphisms that affect the metabolism of mercaptopurine and azathioprine by thiopurine methyltransferase (TPMT) are identified. These polymorphisms are believed to be present in approximately 10% of the white and black populations and, if not identified prior to treatment, can result in severe, life-threatening myelosuppression. 7 Patients with this polymorphism can receive a thiopurine, although the dose must be decreased. Interestingly, the pharmacogenomics test for TPMT activity was one of the first pharmacogenomics tests used clinically. (Detail-Document #210701: Page 2 of 5) Pharmacodynamic Interactions In contrast with pharmacokinetic interactions, most pharmacodynamic interactions are currently not clearly understood. However, it is known that genetic polymorphisms can affect drug targets such as receptors and signal transduction modulators. One pharmacogenomic pharmacodynamic interaction that is understood deals with overexpression of the HER2/neu oncogene. Women with metastatic breast cancer and overexpression of the HER2/neu oncogene appear to derive the greatest benefit from trastuzumab (Herceptin) administration. Additional examples of pharmacodynamic interactions that are not clearly understood include changes in the serotonin neurotransmitter receptor that are associated with clozapine effectiveness and changes in the beta-adrenergic receptors that affect beta-agonist activity. Unfortunately, these pharmacodynamic interactions have not been consistently duplicated and additional studies need to be done. Disease Pathways Probably the least understood mechanism by which genes influence drug response is through disease pathways. This mechanism is complicated by the fact that for many diseases, multiple genes affect the disease pathway. The Factor-V Leiden mutation is an example of how genes can affect a disease pathway and ultimately drug response. Women with this genetic polymorphism are at an increased risk of venous thrombosis if they use oral contraceptives. 5 Conclusions The role of pharmacogenomics in the individualization of drug therapy will likely increase exponentially during the next decades as more rapid and reliable pharmacogenomics tests become available. Currently, the majority of pharmacogenomics information pertains to SNPs; in the future, it is anticipated that the majority of pharmacogenomics information will pertain to polymorphisms in multiple genes. By utilizing the data provided from pharmacogenomics tests, drug therapy can evolve from a one-size fits all approach to a more individualized approach. The end result will hopefully be an improvement in the patient s response to therapy and ultimately decreased healthcare costs.

3 (Detail-Document #210701: Page 3 of 5) 4, 5, 8-13 Table: Pharmacogenomic Examples Drug or Drug Class Protein or gene Clinical Effect Frequency Pharmacokinetic Interactions Antidepressants CYP2D6 Antipsychotics Antiarrhythmics Atomoxetine (Strattera) Greater likelihood of adverse reactions in people who are poor metabolizers; greater likelihood of treatment failure in people who are rapid metabolizers Codeine CYP2D6 Greater likelihood of adverse reactions in people who are rapid metabolizers; greater likelihood of treatment failure in people who are slow metabolizers Beta-blockers CYP2D6 Marked differences in plasma levels reported; clinical significance not currently known Warfarin (Coumadin) Tolbutamide (Orinase) Glipizide (Glucotrol) Phenytoin (Dilantin) Proton pump inhibitors Fluorouracil Capecitabine (Xeloda) Mercaptopurine (Purinethol) Thioguanine (Tabloid) Azathioprine (Imuran) Poor metabolizers Caucasians: 5%-10% Southeast Asians: 1%-2% Kung San Bushmen: 18.8% Ultra-rapid metabolizers Scandinavians: 1% Germans: 3.6% Spaniards:10% Saudi Arabians: 20% Ethiopians:39% CYP2C9 Poor metabolizers may exhibit toxic drug effects Poor metabolizers () Ultra-poor metabolizers Europeans: 0.2% to 1% Southeast Asians: relatively uncommon, close to 0% CYP2C19 Dihydropyridine dehydrogenase (DPD) Thiopurine methyltransferase (TPMT) Marked differences in plasma levels reported; increased gastric and duodenal ulcer healing rates documented in poor metabolizers and decreased rates in ultra-rapid metabolizers Patients with DPD deficiency experience profound toxicity effects including life-threatening gastrointestinal toxicity, myelosuppression, and neurological toxicities Patients with TPMT deficiency experience profound myelosuppression with normal doses Poor metabolizers Caucasians: 2%-3% Blacks: 4% Southeast Asians: 10%-25% Caucasians: 0.9% Japanese, Taiwanese, African Americans: not observed

4 (Detail-Document #210701: Page 4 of 5) 4, 5, 8-13 Table: Pharmacogenomic Examples Drug or Drug Class Protein or gene Clinical Effect Frequency Pharmacokinetic Interactions (cont) Irinotecan (Camptosar) Uridine diphosphate glucuronosyl-transferase 1A1 (UGT1A1) Patients with UGT1A1 deficiency are at an increased risk of developing severe toxicities including gastrointestinal toxicities and neutropenia Pharmacodynamic Interactions Imatinib (Gleevec) bcr-abl tyrosine kinase Administration to patients with chronic myeloid leukemia results in decreased proliferation and survival of leukemia cells Trastuzumab (Herceptin) HER2/neu oncogene Administration to patients with tumor cells that overexpress HER2/neu results in decreased tumor cell proliferation Chinese: 16% Europeans: 40% East Indians: 40% HER2/neu overexpressed in 25% to 30% of primary breast cancers Disease Pathways Abacavir (Ziagen) HLA-B*5701 Increased risk of hypersensitivity reactions Hypersensitivity reactions 114 times more common in patients with HLA-B*5701 allele Oral Contraceptives Tamoxifen (Nolvadex) Factor-V Leiden Increased incidence of deep vein and cerebral vein thrombosis (Tamoxifen included based on preliminary evidence) General anesthetics Ryanodine receptor (RYR1) Increased incidence of malignant hyperthermia in patients with a mutation in the gene for the RYR1 Mutations found in 25% of individuals susceptible to malignant hyperthermia

5 (Detail-Document #210701: Page 5 of 5) Users of this document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and Internet links in this article were current as of the date of publication. References 1. National Center for Biotechnology Information. One size does not fit all: The promise of pharmacogenomics. Available at: ml. (Accessed June 13, 2005). 2. American Medical Association. Pharmacogenomics. Available at: (Accessed June 13, 2005). 3. Montgomery M, Louie S. Pharmacogenomics: What pharmacists need to know. Calif J Health- System Pharm 2001;13: Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352: Maitland-van ZA, Klungel OH, de Boer A. Pharmacogenetics in health-care practice. Pharm World Sci 2004;26: Silber J. New Roche DNA chip could be boon. January 25, Available at: htm. (Accessed June 15, 2005). 7. Norton RM. Pharmacogenomics and individualized drug therapy. Medscape. Available at: search. (Accessed June 13, 2005). 8. Litman RS, Rosenberg H. Malignant hyperthermia: Update on susceptibility testing. JAMA 2005;293: Goetz MP, Ames MM, Weinshilboum RM. Primer on medical genomics. Part XII: Pharmacogenomics--general principles with cancer as a model. Mayo Clin Proc 2004;79: Ansell SM, Ackerman MJ, Black JL, et al. Primer on medical genomics. Part VI: Genomics and molecular genetics in clinical practice. Mayo Clin Proc 2003;78: Dervieux T, Meshkin B, Neri B. Pharmacogenetic testing: Proofs of principle and pharmacoeconomic implications. Mutat Res 2005;573: Evans WE, Relling MV. Moving towards individualized medicine with pharmacogenomics. Nature 2004;429: Graber JE, Halabi S, Kaplan E, et al. Factor V Leiden (FVL) mutations and thromboembolic events (TE) in women with breast cancer on adjuvant tamoxifen ASCO Annual Meeting, Abstract No Available at: (Accessed June 17, 2005). Cite this Detail-Document as follows: Pharmacogenomics: an update. Pharmacist s Letter/Prescriber s Letter 2005;21(7): The most practical knowledge in the least time 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Subscribers to Pharmacist s Letter and Prescriber s Letter can get Detail-Documents, like this one, on any topic covered in any issue by going to or