Role of CYP2C19 Polymorphism in the Drug Interaction Between Clopidogrel and Omeprazole

Clopidogrel, an inhibitor of ADP induced platelet aggregation and activation, is one of the
most commonly used drugs in patients with cardiovascular disease; coronary-stenting would not
be possible without the robust anti platelet function of this drug. Clopidogrel is a pro-drug
that is transformed through a series of hepatic cytochrome p-450 (CYP) enzymes to an active
metabolite. One of these CYP enzymes, 2C19 is subject to competitive inhibition by commonly
used proton-pump inhibitors (PPIs). PPIs are commonly used for gastro-esophageal protection
in patients treated with clopidogrel. Around 63% of 3,799 patients on clopidogrel received a
PPI at TMH in 2008.

Recently, a series of publications indicated that clopidogrel active metabolite levels and
platelet inhibition are lower in patients receiving PPIs. In addition, a recent survey of
>16,690 patients in Medco database indicates that use of PPIs is associated with a 51%
increase in the risk of death or myocardial infarction in patients receiving clopidogrel.
Recent data have also indicated that patients with loss of function (LOF) haplotypes of the
CYP2C19 gene have lower levels of the active metabolite after dosing with clopidogrel. These
patients have higher rates of death, myocardial infarction, stent thrombosis and other
ischemic complications than do patients with the wild type enzyme. Inadequate responses to
clopidogrel therapy have been implicated as an important predictor of adverse clinical
events. The reported prevalence of non-responsiveness to clopidogrel among patients with
cardiovascular disease is between 4% and 34%, depending on the method and definition used to
assess this parameter. Approximately 25% of American population carries a LOF mutation of
CYP2C19.

It is unclear whether the concomitant use of omeprazole (PPI) with clopidogrel would result
in a decrease in platelet function parameters through the CYP2C19 clopidogrel activation
pathway. The specific aim of the proposed study is to determine whether the interaction
between PPIs and clopidogrel is dependent on CYP2C19 haplotype. We hypothesize that among
subjects with a LOF genotype, the interaction between clopidogrel and PPIs is greater than
that in subjects with the wild type genotype7 and is manifest in both platelet function
parameters and in conversion of clopidogrel to its active metabolite.

Approximately 75 randomly selected healthy volunteer subjects will be screened with the
intent of identifying at least 16 subjects who are heterozygous for a LOF mutation of CYP2C19
(known as *2/rs4244285, *3).

Subjects with the LOF allele will be selected along with age and gender-matched wild type
controls and baseline platelet function studies will be performed (n=16 for each group).
Subjects in each stratum will then be randomly assigned to receive one week of clopidogrel in
combination with omeprazole or clopidogrel alone. Subjects initially assigned to clopidogrel
+ omeprazole will then take clopidogrel only and subjects initially assigned to clopidogrel
only will take both clopidogrel and omeprazole.

Inclusion Criteria:

- age 18- 65

- healthy - not taking any drugs / over the counter drugs regularly.

- ability and commitment to take the drugs and volunteer for 3 blood draws.

Exclusion Criteria:

- Taking any scheduled medication known to affect platelet function such as clopidogrel
or NSAIDS11, COX2 inhibitors, beta blockers, calcium channel blockers, diuretics,
anti-coagulants, older psychotropic agents, and recent ingestion of alcohol and
caffeine

- Known history of heart disease

- Bleeding disorders

- Known allergy or contraindications to omeprazole or clopidogrel

- Pregnant and nursing women will also be excluded.