Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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278 Applying Pharmacogenomics in TherapeuticsHER2 and TrastuzumabHuman epidermal growth factor receptor-2 (HER2) was identified as a potentialmonoclonal antibody target in the early 1980s, and thereafter the humanizedIgG1 monoclonal antibody trastuzumab moved into clinical trials in 1992 and wasapproved by the US FDA as Herceptin in 1998 and by the EMEA’s centralized procedurein 2000, respectively. Herceptin, specifically developed to target the receptorHER2 and to cause cell death, is an anticancer target therapy for use in patients withbreast cancer who are HER2-positive. Genetic testing helps identify overexpressionof HER2. There are two different commercial testing kits currently available in themarket: one is immunohistochemistry (IHC) testing (which detects overexpressionof HER2 protein/antigen in breast cancer tissue) and the other is cytogenetic fluorescentin situ hybridization (FISH) testing (which detects amplification of the geneencoding the HER2), both of which have been approved by the US FDA for detectionof HER2 overexpression. The use of the HER2 testing has been required in the druglabeling of trastuzumab treatment. In Europe (United Kingdom, Ireland, Germany,and the Netherlands), HER2 testing was performed in approximately 84% of breastcancer women who received trastuzumab treatment, indicating a larger consensuson the clinical utility of HER2 testing in that clinical setting. 1 Because HER2 testingservice can identify who would be good responders to trastuzumab treatment, thistesting can reduce inefficacious use of trastuzumab in some breast cancer patientsbefore they receive that biologic. According to a multicenter survey in Europe, 1 theclinical utility is perceived with a higher level of implementation of HER2 testing,and the benefits of HER2 testing clearly outweigh its costs, as measured with costper life years gained, improved life expectancy, or the number of deaths averted. Inaddition, HER2 is thought to be a biomarker that has both clinical validity and utilitydue to significantly improved patient care. 14HLA B*5701 and Abacavir HypersensitivityAbacavir, an HIV reverse transcriptase inhibitor, is often used in combinationwith other antivirals in the treatment of HIV infection. Hypersensitivity reactionsto abacavir occur in approximately 5% of HIV-infected patients taking the drug,which may result in potentially life-threatening hypotension if drug therapy is notceased. 34 Clinical research studies have also indicated that patients with the humanleukocyte antigen HLA B*5701 are at greater risk of a hypersensitivity reactionto abacavir. 19,20 In terms of the higher prevalence of the HLA B*5701 (9–18%), anestablished genotype–phenotype association, the low cost of HLA B*5701 testing(e.g. $62), and the high cost to treat abacavir-induced hypersensitivity (e.g., $3730),HLA B*5701 testing before drug therapy would be most likely in a cost-effectivefashion. 21 Another study also indicated that the ICE ratio of HLA genotyping wascost savings of up to $32,500 per hypersensitivity reaction avoided. 16 Therefore,HLA genotyping is considered cost-effective as anticipated, 21 according to a reasonablecutoff value of less than US$50,000 per QALY gained. 7,9,10,17 Furthermore,HLAB*5701 is considered to have both clinical validity and clinical utility, whichlead to improved patient outcomes. 14
Pharmacoeconomics of Pharmacogenomics279CYP2C9 and the Anticoagulant WarfarinWarfarin anticoagulation therapy is increasing rapidly in the elderly population becauseof the increasing prevalence of atrial fibrillation and longer life spans. In 2007, morethan 20 million new prescriptions were written for this drug in the United States,according to the National Institutes of Health. Initiation and maintenance therapy ofwarfarin is difficult because of wide intersubject variability in its dose requirements andresponse, and thus warfarin dosing is monitored and adjusted to maintain appropriateprothrombin time and international normalized ratio within a target range of 2–3 foreach patient. Warfarin is one of the first medications to be relabeled by the US FDA toexplain why an individual’s genetic make-up could affect response to the drug, and PGxtesting for warfarin is one of the first such tests to get US FDA approval.Although warfarin is a generic medication that is relatively inexpensive and the costof testing for CYP2C9 and VKORC1 also seems to be relatively less expensive (rangingfrom $250 to $630), the main cost of warfarin dosing is the healthcare spendingassociated with bleeding complications and death, in particular during the first fewmonths of warfarin initiation therapy to titrate warfarin doses. Because adverse eventsassociated with warfarin therapy are common, and many are preventable through agenotype-guided algorithm, the number of patients who could benefit more from thePGx testing would be large, suggesting the presence of potential cost-effectiveness forgenotyping. In 34 eligible pharmacoeconogenomic articles published from 1999 to2009, CYP2C9 alone or in combination with VKORC1 (vitamin K epoxide reductasecomplex subunit 1) are the most common genes that were evaluated in the clinicalsettings. 14 CYP2C9*2 or *3 variant alleles are associated with reduced maintenancedose requirements of warfarin therapy and increased risk of major bleeding events; 35,36the marginal cost per additional major bleeding event averted was estimated to be$5778 for CYP2C9 genotype-guided dosing of warfarin, 37 and €4233 for CYP2C9 genotype-guideddosing of acenocoumarol. 38 Testing of CYP2C9*2, *3 and VKORC1 A/Abefore receiving warfarin was considered to have clinical validity 39 but unclear clinicalutility. 40,41 However, in atrial fibrillation patients treated with warfarin, the cost perQALY gained was $60,725 and $170,000 for CYP2C9 and VKORC1 genotype-guideddosing, respectively, 42,43 suggesting little cost-effectiveness. Currently, the US Centersfor Medicare and Medicaid Services have not found sufficient evidence to cover the costof genotyping for warfarin dosing. 44 In the future, multicenter, large-scale, prospective,randomized clinical trials will be required to confirm whether genotype-guided warfarindosing would be less costly and more effective than its conventional regimen.CYP2C19 and the Antiplatelet Drug ClopidogrelClopidogrel is a prodrug whose bioactivation is dependent largely on CYP2C19activity in the liver (Figure 11.1), and thus the CYP2C19 genotype is the major predictorof adverse cardiovascular events in clopidogrel-treated patients with acutecoronary syndrome (ACS) or those undergoing percutaneous coronary intervention(PCI). 45 In 2010, the US FDA consecutively released the black box warning threetimes for the clopidogrel labeling, alerting clinicians of the role of CYP2C19*2 and*3 loss-of-function variants in response to that drug in patient care. Although the
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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