Clopidogrel Pharmacogenetics (PGX) Bench to Bedside (PGXB2B)

Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application

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.

Study Overview

• Status: Completed
• Conditions: Metabolism of Clopidogrel
• Intervention / Treatment: Drug: Clopidogrel; Drug: Omeprazole/Clopidogrel

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17601
      • Amish Research Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clopidogrel in 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 (PM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). 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.	Drug: Clopidogrel; 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.; Other Names: Plavix
Experimental: Clopidogrel in 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 (IM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). 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.	Drug: Clopidogrel; 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.; Other Names: Plavix
Experimental: Clopidogrel in 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 (EM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study (NCT 00799396). 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.	Drug: Clopidogrel; 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.; Other Names: Plavix
Experimental: Omeprazole/Clopidogrel in PM; PM participants who have completed Arm 1 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.	Drug: Omeprazole/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.; Other Names: Plavix; Prilosec
Experimental: Omeprazole/Clopidogrel in IM; IM participants who have completed Arm 2 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.	Drug: Omeprazole/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.; Other Names: Plavix; Prilosec
Experimental: Omeprazole/Clopidogrel in EM; EM participants who have completed Arm 3 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.	Drug: Omeprazole/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.; Other Names: Plavix; Prilosec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Platelet Aggregation Following Therapy With Clopidogrel	Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1.	Day 1, 4 hours post clopidogrel dose
Change in Platelet Aggregation Following Therapy With Clopidogrel	ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose	4 hours post Day 8 dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Baseline, Day 8
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.	Baseline, 0.25, 0.5, 1, 2, and 4 hours

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Food and Drug Administration (FDA); National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Richard B Horenstein, M.D., University of Maryland, Baltimore

Publications and helpful links

General Publications

• Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.
• Jiang XL, Samant S, Lewis JP, Horenstein RB, Shuldiner AR, Yerges-Armstrong LM, Peletier LA, Lesko LJ, Schmidt S. Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults. Eur J Pharm Sci. 2016 Jan 20;82:64-78. doi: 10.1016/j.ejps.2015.10.024. Epub 2015 Oct 30.
• Horenstein RB, Madabushi R, Zineh I, Yerges-Armstrong LM, Peer CJ, Schuck RN, Figg WD, Shuldiner AR, Pacanowski MA. Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. J Clin Pharmacol. 2014 Aug;54(8):865-73. doi: 10.1002/jcph.293. Epub 2014 Apr 7.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: April 22, 2011
• First Submitted That Met QC Criteria: April 22, 2011
• First Posted (Estimated): April 25, 2011

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacogenetics; Healthy Subjects; Platelets; Clopidogrel
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Clopidogrel; Omeprazole
• Other Study ID Numbers: HP-00044487; U01GM074518 (U.S. NIH Grant/Contract); U01HL105198 (U.S. NIH Grant/Contract); 128475 (Other Grant/Funding Number: NIH); ZICSC006536 (U.S. NIH Grant/Contract); ZICSC006537 (U.S. NIH Grant/Contract)