Clopidogrel PGX Bench to Bedside (PGXB2B)
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Purpose
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.
| Condition | Intervention |
|---|---|
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Metabolism of Clopidogrel |
Drug: Clopidogrel, Omeprazole |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application |
- Change in platelet aggregation following therapy with Clopidogrel [ Time Frame: Baseline, Day 1, Day 8 ] [ Designated as safety issue: Yes ]platelet aggregation will be measured at baseline and at 4-hours post-dose of clopidogrel on day 1 and at 4-hours post-dose of clopidogrel on day 8. The primary endpoint of this study will be the change in maximal platelet aggregation 4-hours post-dose (MPA4; units are a percentage) on day 8 of each study period compared to baseline.
- 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
| Enrollment: | 18 |
| Study Start Date: | July 2010 |
| Study Completion Date: | May 2011 |
| Primary Completion Date: | May 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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.
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Drug: Clopidogrel, Omeprazole
Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. Other Names:
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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
|
Drug: Clopidogrel, Omeprazole
Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. Other Names:
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|
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
|
Drug: Clopidogrel, Omeprazole
Over a 6 week period participants will be given: 75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. Other Names:
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Detailed Description:
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.
Eligibility| Ages Eligible for Study: | 20 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
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
Contacts and Locations| United States, Pennsylvania | |
| Amish Research Clinic | |
| Lancaster, Pennsylvania, United States, 17601 | |
| Principal Investigator: | Richard B Horenstein, M.D. | University of Maryland |
More Information
Publications:
| Responsible Party: | Alan Shuldiner, Professor of Medicine, University of Maryland |
| ClinicalTrials.gov Identifier: | NCT01341600 History of Changes |
| Other Study ID Numbers: | HP-00044487, 3U01GM074518-05S1 |
| Study First Received: | April 22, 2011 |
| Last Updated: | September 28, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by University of Maryland:
|
Clopidogrel Pharmacogenetics Platelets Healthy Subjects |
Additional relevant MeSH terms:
|
Omeprazole Clopidogrel Ticlopidine Anti-Ulcer Agents Gastrointestinal Agents Therapeutic Uses Pharmacologic Actions Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Platelet Aggregation Inhibitors |
Hematologic Agents Purinergic P2Y Receptor Antagonists Purinergic P2 Receptor Antagonists Purinergic Antagonists Purinergic Agents Neurotransmitter Agents Physiological Effects of Drugs Fibrinolytic Agents Fibrin Modulating Agents Cardiovascular Agents |
ClinicalTrials.gov processed this record on May 16, 2013