Biomedical Engineering Reference
In-Depth Information
Fig. 3
Representative ion chromatograms for the LC/TOF MS analysis of (
a
) clopidogrel,
(
b
) inactive metabolite, and (
c
) active metabolite. The latter is derivatized with 2-bromo-3ยข -
methoxyacetophenone. Separate injections were necessary for the active vs. inactive metabolite
due to the need to derivatize the biologically active clopidogrel form
There have been several clinical studies on the effect of CYP 2C19 carriers of at
least one loss of function alleles. In the TRITON-TIMI39 study, carriers had a rela-
tive increase of 53 % in the incidence of death from cardiovascular disease, myocar-
dial infarction, or stroke compared to noncarriers and a threefold higher risk of stent
thrombosis [
16
]. In the Collet study among young patients, the hazard ratios (HR)
were 3.69 and 6.02 (
p
< 0.05) for cardiac events and stent thrombosis, respectively
[
17
]. Similar findings were also reported by Giusti et al. (HR = 2.36 and 2.59 for
mortality and stent thrombosis, respectively,
p
< 0.05) [
18
]. Based on these and other
reports, the US Food and Drug Administration (FDA) issued a Black Box warning
in March 2010 on the use of clopidogrel, addressing the need for pharmacogenomic
testing [
19
]. While it was appropriate for the FDA to issue this warning, there is
insufficient evidence to date to recommend the actions taken (e.g., higher clopi-
dogrel dosing or use of an alternative medication) for individuals who are deter-
mined to be at risk [
20
]. Such guidance will likely follow with completion of
ongoing randomized trials addressing these issues. GRAVITAS was a randomized
clinical trial of 75 mg vs. 150 mg clopidogrel for individuals who are resistant to
clopidogrel by platelet aggregometry, with 1 and 6-month outcomes recorded [
21
] .
Recently, the CYP 2C19
*17
variant was identified as having increased transcrip-
tional activity, resulting in ultrarapid metabolism. For clopidogrel, the consequence is
