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

Essential Pharmacogenomic Biomarkers in Clinical Practice
59
severe bleeding, thus requiring lower starting doses. 40–42 Notably, there are significant
population differences in the frequencies of the CYP2C9 alleles with *2 allele
more common in Caucasian than Asian or African populations, while the *3 allele is
less common in all ethnic groups and is extremely rare in African populations. 43–45
Other alleles such as CYP2C9*5, *6, and *8 may contribute to the variability in
African American patient response to warfarin. 46 Therefore, a patient’s CYP2C9 and
VKORC1 genotypes may be used clinically to help determine the optimal starting
dose of warfarin. The United States Food and Drug Administration (FDA)–approved
warfarin drug label now provides a dosing table that is derived from multiple clinical
studies, which recommends that warfarin initial doses vary between the patients
based on their combinations of CYP2C9 and VKORC1 genotypes.
Clopidogrel
Clopidogrel, an antiplatelet prodrug, can specifically inhibit platelet activation and
aggregation through blockade of the adenosine diphosphate (ADP) receptor P2Y12
expressed on platelets after its metabolic activation in the liver. Clopidogrel is a
commonly prescribed drug used to prevent thrombotic events after myocardial
infarction, ischemic stroke, and coronary stent placement. Serious ADRs have been
associated with clopidogrel, including severe neutropenia, hemorrhage, and thrombotic
thrombocytopenic purpura. 47 CYP2C19 (cytochrome P450, family 2, subfamily
C, polypeptide 19) is one of the principal enzymes involved in the metabolism
of clopidogrel. Pharmacogenetic studies have demonstrated the importance of
CYP2C19 genotypes in clopidogrel treatment. For example, carriers of CY2C19 lossof-function
alleles, for example, CYP2C19*2, were found to have significantly lower
levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a
higher rate of major adverse cardiovascular events (MACEs) than did noncarriers of
these alleles. 48,49 Among patients treated with clopidogrel for percutaneous coronary
intervention, carriage of even one reduced-function CYP2C19 allele was found to be
associated with a significantly increased risk of MACEs, particularly stent thrombosis.
50 The CYP2C19*2 variant was also found to be a major determinant of prognosis
in young patients who were receiving clopidogrel treatment after myocardial infarction.
51 The US FDA recommends that CYP2C19 genotyping be considered prior to
prescribing clopidogrel, although the association between the CYP2C19 genotypes
and cardiovascular events is still controversial. 52,53
Simvastatin
Simvastatin is used to control elevated cholesterol in blood, or hypercholesterolemia
and the prevention of cardiovascular diseases. 54 Common side effects of simvastatin
include abdominal pain, diarrhea, indigestion, and a general feeling of weakness.
In rare cases, myopathy may occur in association with statin treatments, especially
when the statins are administered at higher doses (80 mg of simvastatin daily vs.
standard doses of 20–40 mg daily) and in combination with certain other drugs
(cyclosporine). 55 A genome-wide pharmacogenomic scan has been performed to
evaluate the genetic contribution to simvastatin-induced myopathy in patients with
prior myocardial infarction in a clinical trial to determine whether a daily dose of
80 mg of simvastatin safely produces greater benefits than does a daily dose of 20 mg