Clopidogrel PGX Bench to Bedside (PGXB2B)

• Change in platelet aggregation following therapy with Clopidogrel and Omeprazole [ Time Frame: Baseline, Day 8 ] [ Designated as safety issue: Yes ]
  The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole will be compared to the baseline measure of platelet aggregation at day 1 prior to drug therapy
• Level of active clopidogrel metabolite [ Time Frame: Baseline, 4 hours ] [ Designated as safety issue: Yes ]
  The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the dose is administered for pharmacokinetic analysis

• Change in Platelet Aggregation following therapy with Clopidogrel and Omeprazole [ Time Frame: 8 days ] [ Designated as safety issue: Yes ]
  The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole.
• Level of active clopidogrel metabolite [ Time Frame: Day 1 ] [ Designated as safety issue: Yes ]
  The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the dose is administered for pharmacokinetic analysis.

Clopidogrel (also known as Plavix) is used commonly in patients to prevent heart attacks and conditions caused by blood clots. Although clopidogrel works in many individuals, some people do not respond as well to this drug. The variation in treatment response may be linked to genetics. This study will examine the effects of clopidogrel in a population whose genes are well known in order to determine the role that genes play in the response to various clopidogrel maintenance doses.

Clopidogrel is a prodrug with high inter-individual response variability. Clopidogrel is converted to an active drug through an enzyme encoded by the gene named CYP2C19. Individuals with genetically-impaired CYP2C19 metabolism have lower capacity to convert the prodrug to its active form. Consequently, these individuals have lower blood levels of the activated form of clopidogrel, diminished antiplatelet responses, and higher rates of cardiovascular events and stent thrombosis. Increasing doses of clopidogrel in such patients represents a possible approach to managing the gene-drug interaction.

The purpose of this study is to evaluate whether increasing the dose of clopidogrel increases antiplatelet responses and active metabolite exposure in individuals with genetically reduced CYP2C19 metabolism relative to those with normal CYP2C19 metabolism.

The primary objective is to assess changes in clopidogrel response and exposure at three clopidogrel dose levels and with coadministration of omeprazole.

• Experimental: poor metabolizers
  Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers to clopidogrel 75 mg from participants who previously received clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study.
  Intervention: Drug: Clopidogrel, Omeprazole
• Experimental: intermediate metabolizers
  Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI
  Intervention: Drug: Clopidogrel, Omeprazole
• Experimental: extensive metabolizers
  Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI
  Intervention: Drug: Clopidogrel, Omeprazole

Inclusion Criteria:

• Amish men or women between 20 and 70 years of age who participated in PAPI

Exclusion Criteria:

• Severe hypertension (bp > 160/95 mm Hg)
• Co-existing malignancy
• AST or ALT > 2 times normal
• Creatinine >2.0
• Hct < 32 or Hct > 50
• TSH < 0.40 or >5.50
• History of bleeding disorder or gastrointestinal bleeding
• History of unstable angina, MI, angioplasty, coronary artery bypass surgery
• History of atrial fibrillation, stroke or transient ischemic attacks or deep vein thrombosis
• Type 2 diabetes
• Thrombocytosis (platelet count > 500,000) or thrombocytopenia (platelet count < 150,000)
• Surgery within six months
• Clopidogrel allergy
• Pregnant women
• Currently breast feeding
• Omeprazole allergy
• Prospective participants taking medications that would affect the outcome(s) to be measured and who cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation, or who are taking vitamins and/or other supplements and who are unwilling to discontinue their use for at least 1 week prior to study

• Food and Drug Administration (FDA)
• National Cancer Institute (NCI)
• National Institute of General Medical Sciences (NIGMS)