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

194 Applying Pharmacogenomics in Therapeutics
used to improve healthcare. These include the warfarin trials and efforts such as
the Pharmacogenomics Research Network and the Electronic Medical Records
and Genomics Network. Identifying outcomes and analyzing costs are other
challenges. The questions surrounding genotype testing for warfarin and clopidogrel
dosing include the following: Will testing help improve outcomes? Will the
costs of testing be offset by the benefits? For warfarin, dosing recommendations
for different genotypes are derived from the results of clinical studies. And there
are 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 that
dosing according to genotype is better than careful INR monitoring and dose
adjustment. For clopidogrel, there are no data on dosing or treatment strategies
to improve outcomes based on genotype. Medical practitioners also question the
value of adding genetic testing while INRs are being routinely monitored. Critics
of the black box warning for clopidogrel argue that clinicians have no specific
guidance for responding to the warning. Despite extensive research, much of the
research in cardiovascular pharmacogenomics remains in the discovery phase,
with researchers struggling to demonstrate clinical utility and validity because of
poor study design, inadequate sample sizes, lack of replication, and heterogeneity
across the patient populations and phenotypes. In order to progress pharmacogenetics
in cardiovascular therapies, researchers need to utilize next-generation
sequencing technologies, develop clear phenotype definitions, and engage in multicenter
collaborations. These efforts do not need larger sample sizes but have to
replicate associations and confirm results across different ethnic groups.
STUDY QUESTION
DV is a 65-year-old man who recently had an acute myocardial infarction (MI).
To prevent subsequent ischemic events, DV’s physician recommends antiplatelet
therapy and prescribes clopidogrel. His current medications included amlodipine
10 mg daily, hydrochlorothiazide 25 mg daily, aspirin 81 mg daily, pravastatin
40 mg daily, metformin ER 850 mg daily, and clopidogrel 75 mg daily. Four
months later, DV suffered another acute MI, and his physician suspects that the
patient has not been taking his medications as directed, or alternatively, that clopidogrel
therapy may have been unsuccessful. How would genetic testing benefit DV
and his physician?
Answer
Clopidogrel is a prodrug, and in order to be active in vivo, it must be transformed
to a more active metabolite. CYP2C19 is responsible for its metabolic activation,
and CYP2C19 loss of activity alleles appear to be associated with higher rates of
recurrent cardiovascular events in patients receiving clopidogrel. CYP2C19 poor
metabolizer 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 liver
enzyme CYP2C19 is primarily responsible for the formation of the active metabolite
of clopidogrel. Pharmacokinetic and antiplatelet tests of the active metabolite of