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

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194 Applying Pharmacogenomics in Therapeuticsused to improve healthcare. These include the warfarin trials and efforts such asthe Pharmacogenomics Research Network and the Electronic Medical Recordsand Genomics Network. Identifying outcomes and analyzing costs are otherchallenges. The questions surrounding genotype testing for warfarin and clopidogreldosing include the following: Will testing help improve outcomes? Will thecosts of testing be offset by the benefits? For warfarin, dosing recommendationsfor different genotypes are derived from the results of clinical studies. And thereare data to suggest that hospitalizations could be reduced with genotype testing.However, there is no evidence that testing is cost-effective, and it is not clear thatdosing according to genotype is better than careful INR monitoring and doseadjustment. For clopidogrel, there are no data on dosing or treatment strategiesto improve outcomes based on genotype. Medical practitioners also question thevalue of adding genetic testing while INRs are being routinely monitored. Criticsof the black box warning for clopidogrel argue that clinicians have no specificguidance for responding to the warning. Despite extensive research, much of theresearch in cardiovascular pharmacogenomics remains in the discovery phase,with researchers struggling to demonstrate clinical utility and validity because ofpoor study design, inadequate sample sizes, lack of replication, and heterogeneityacross the patient populations and phenotypes. In order to progress pharmacogeneticsin cardiovascular therapies, researchers need to utilize next-generationsequencing technologies, develop clear phenotype definitions, and engage in multicentercollaborations. These efforts do not need larger sample sizes but have toreplicate associations and confirm results across different ethnic groups.STUDY QUESTIONDV is a 65-year-old man who recently had an acute myocardial infarction (MI).To prevent subsequent ischemic events, DV’s physician recommends antiplatelettherapy and prescribes clopidogrel. His current medications included amlodipine10 mg daily, hydrochlorothiazide 25 mg daily, aspirin 81 mg daily, pravastatin40 mg daily, metformin ER 850 mg daily, and clopidogrel 75 mg daily. Fourmonths later, DV suffered another acute MI, and his physician suspects that thepatient has not been taking his medications as directed, or alternatively, that clopidogreltherapy may have been unsuccessful. How would genetic testing benefit DVand his physician?AnswerClopidogrel is a prodrug, and in order to be active in vivo, it must be transformedto a more active metabolite. CYP2C19 is responsible for its metabolic activation,and CYP2C19 loss of activity alleles appear to be associated with higher rates ofrecurrent cardiovascular events in patients receiving clopidogrel. CYP2C19 poormetabolizer status is associated with diminished antiplatelet response to clopidogrel.At least one loss-of-function allele is carried by 24% of the white non-Hispanic population,18% of Mexicans, 33% of African Americans, and 50% of Asians. 54 The liverenzyme CYP2C19 is primarily responsible for the formation of the active metaboliteof clopidogrel. Pharmacokinetic and antiplatelet tests of the active metabolite of
Drug Therapy of Cardiovascular Diseases195clopidogrel show that the drug levels and antiplatelet effects differ depending on thegenotype of the CYP2C19 enzyme.The following represent the different alleles of CYP2C19 that make up a patient’sgenotype:• The CYP2C19*1 allele has fully functional metabolism of clopidogrel.• The CYP2C19*2 and *3 alleles have no functional metabolism of clopidogrel.These two alleles account for most of the reduced function allelesin patients of Caucasian (85%) and Asian (99%) descent classified as poormetabolizers.• The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associatedwith absent or reduced metabolism of clopidogrel but are less frequent thanthe CYP2C19*2 and *3 alleles. 55Noticing DV’s CYP2C19 genotype may reveal that he carries a variant thatdiminishes the antiplatelet effect of clopidogrel. If this were the case, alternativeantiplatelet therapies may have been considered, reducing the chance that DV wouldsuffer a second cardiac event. Homozygous carriers, who are poor CYP2C19 metabolizers,make up 3–4% of the population. A current FDA-boxed warning states thatpoor CYP2C19 metabolizers may not benefit from clopidogrel and recommends thatprescribers consider alternative treatment for patients in this category. However, routineCYP2C19 testing is not recommended, and no firm recommendations have beenestablished regarding dose adjustments for CYP2C19 status.Clinicians should be aware that the low exposure seen in poor metabolizers alsooccurs in patients taking drugs that inhibit CYP2C19. 54 Although a higher dose regimen(600 mg loading dose followed by 150 mg once daily) in poor metabolizersincreases antiplatelet response, an appropriate dose regimen for this patient populationhas not been established in a clinical outcome trial. Switching to prasugrel(Effient) is also another alternative to this problem.ACKNOWLEDGMENTThe author acknowledge the contributions of Drs Anahita Malekakhlagh and CarolineForrester.REFERENCES1. Wilkinson G. (2005). Drug metabolism and variability among patients in drug response.New England Journal of Medicine, 352: 2211–2221.2. Wadelius M, Pirmohamed M. (2007). Pharmacogenetics of warfarin: Current statusand future challenges. Pharmacogenomics Journal, 7: 99–111.3. PharmGKB. Warfarin pathway pharmacokinetics: Representation of the candidategenes involved in transport, metabolism and clearance of warfarin. Palo Alto, CA:Stanford University. Available from: http://www.pharmgkb.org/pathway/PA145011113(accessed February 24, 2012).4. Voora D, McLeod HL, Elby C, Gage BF. (2005). The pharmacogenetics of coumarintherapy. Pharmacogenomics, 6: 503–513.
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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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11 PharmacoeconogenomicsA Good Marr
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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