Metabolism of Clopidogrel
Conditions
Keywords
Clopidogrel, Pharmacogenetics, Platelets, Healthy Subjects
Brief summary
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 in which sequencing for certain genes has been performed in order to determine the role that genes play in the response to various clopidogrel maintenance doses.
Detailed description
Clopidogrel is a prodrug with high inter-individual response variability. Clopidogrel is converted to an active drug in part 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.
Interventions
DRUGClopidogrel
Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days.
DRUGOmeprazole/Clopidogrel
After a washout of at least 1 week, participants will have the option to participate in a final intervention in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.
Sponsors
Food and Drug Administration (FDA)
National Cancer Institute (NCI)
National Institute of General Medical Sciences (NIGMS)
National Heart, Lung, and Blood Institute (NHLBI)
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 70 Years
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 * Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) \> 2 times normal * Creatinine \>2.0 * Hct \< 32 or Hct \> 50 * Thyroid Stimulating Hormone (TSH) \< 0.40 or \>5.50 * History of bleeding disorder or gastrointestinal bleeding * History of unstable angina, myocardial infarction (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Platelet Aggregation Following Therapy With Clopidogrel | Day 1, 4 hours post clopidogrel dose | Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | Baseline, Day 8 | 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 | Baseline, 0.25, 0.5, 1, 2, and 4 hours | The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the Day One dose is administered for pharmacokinetic analysis. The analysis will measure the Area Under the Curve. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 (NCT 00799396).
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. | 6 |
| 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 (NCT 00799396).
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. | 6 |
| 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 (NCT 00799396).
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. | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Poor Metabolizers | Intermediate Metabolizers | Extensive Metabolizers | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 6 Participants | 18 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 6 participants | 18 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 1 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Change in Platelet Aggregation Following Therapy With Clopidogrel
Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1.
Time frame: Day 1, 4 hours post clopidogrel dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 63.2 percentage of aggregation | Standard Deviation 9.3 |
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 62.9 percentage of aggregation | Standard Deviation 14.7 |
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 53.3 percentage of aggregation | Standard Deviation 15.2 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 57.8 percentage of aggregation | Standard Deviation 7.2 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 68.1 percentage of aggregation | Standard Deviation 5 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 47.8 percentage of aggregation | Standard Deviation 13.6 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 62.5 percentage of aggregation | Standard Deviation 3.4 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 38.6 percentage of aggregation | Standard Deviation 10.9 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 53.9 percentage of aggregation | Standard Deviation 12.9 |
Primary
Change in Platelet Aggregation Following Therapy With Clopidogrel
ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose
Time frame: 4 hours post Day 8 dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 44.2 percentage of aggregation | Standard Deviation 15 |
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 55.0 percentage of aggregation | Standard Deviation 14.5 |
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 32.6 percentage of aggregation | Standard Deviation 10.7 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 33.2 percentage of aggregation | Standard Deviation 6 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 37.8 percentage of aggregation | Standard Deviation 8.2 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 25.7 percentage of aggregation | Standard Deviation 6 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 75mg | 31.3 percentage of aggregation | Standard Deviation 7.3 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 300mg | 19.5 percentage of aggregation | Standard Deviation 6.9 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel | Clopidogrel 150mg | 25.1 percentage of aggregation | Standard Deviation 7.1 |
Secondary
Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole
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
Time frame: Baseline, Day 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Poor Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | 11.6 percentage of aggregation | Standard Deviation 11.9 |
| Intermediate Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | 27.9 percentage of aggregation | Standard Deviation 9.3 |
| Extensive Metabolizers | Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | 37.5 percentage of aggregation | Standard Deviation 3.2 |
Secondary
Level of Active Clopidogrel Metabolite
The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the Day One dose is administered for pharmacokinetic analysis. The analysis will measure the Area Under the Curve.
Time frame: Baseline, 0.25, 0.5, 1, 2, and 4 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Poor Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 150mg | 24.2 ng h/mL | Standard Deviation 26 |
| Poor Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 75mg | 17.4 ng h/mL | Standard Deviation 19 |
| Poor Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 300mg | 36 ng h/mL | Standard Deviation 35 |
| Intermediate Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 150mg | 43.8 ng h/mL | Standard Deviation 35 |
| Intermediate Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 75mg | 33.3 ng h/mL | Standard Deviation 37 |
| Intermediate Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 300mg | 73.7 ng h/mL | Standard Deviation 53 |
| Extensive Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 75mg | 32.7 ng h/mL | Standard Deviation 25 |
| Extensive Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 300mg | 80.4 ng h/mL | Standard Deviation 24 |
| Extensive Metabolizers | Level of Active Clopidogrel Metabolite | Clopidogrel 150mg | 53.6 ng h/mL | Standard Deviation 35 |