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. The specific aim of the proposed study is to determine whether the interaction between proton-pump inhibitors (PPIs) and clopidogrel is dependent on CYP2C19 haplotype.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Clopidogrel 75mg, Omeprazole 20mg

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 75

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Healthy subjects aged 18-65.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Crossover
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
wild / normal type allele of CYP2C gene; clopidogrel 75 mg alone.	Drug: Clopidogrel 75mg, Omeprazole 20mg; Clopidogrel and or Omeprazole as applicable; Other Names: Plavix , Prilosec OTC
wild / normal type allele of CYP2C; clopidogrel 75 mg + omeprazole 20 mg.	Drug: Clopidogrel 75mg, Omeprazole 20mg; Clopidogrel and or Omeprazole as applicable; Other Names: Plavix , Prilosec OTC
Loss of Haplotype CYP2C19; clopidogrel 75mg alone	Drug: Clopidogrel 75mg, Omeprazole 20mg; Clopidogrel and or Omeprazole as applicable; Other Names: Plavix , Prilosec OTC
Loss of function haplotype of CYP2C; clopidogrel 75mg + omerprazole 20mg.	Drug: Clopidogrel 75mg, Omeprazole 20mg; Clopidogrel and or Omeprazole as applicable; Other Names: Plavix , Prilosec OTC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of omeprazole on platelet inhibition by clopidogrel	To test whether concomitant administration of omeprazole will decrease the platelet inhibitory properties of clopidogrel in subjects with LOF mutation of CYP2C19 (known as *2 and *3)	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The effect of omeprazole on the conversion of clopidogrel	To test whether concomitant administration of omeprazole will decrease the conversion of clopidogrel to its active metabolite in subjects with loss of function (LOF) mutation of CYP2C19 (known as *2 and *3)	3 weeks

Collaborators and Investigators

• Sponsor: Neil Kleiman, MD

Publications and helpful links

General Publications

• Srinivas Nadipalli, Sashidar Guthikonda, Timothy R. DelaO, Ali J. Marian, Federico Monzon, Ping Wang, Neal S. KleimanDOES A LOSS OF FUNCTION POLYMORPHISM OF CYP2C19 MODULATE THE EFFECTS OF CLOPIDOGREL. J Am Coll Cardiol. 2011;57 E1201.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): June 30, 2014
• Study Completion (Actual): June 30, 2014

Study Registration Dates

• First Submitted: February 10, 2010
• First Submitted That Met QC Criteria: March 25, 2010
• First Posted (Estimate): March 26, 2010

Study Record Updates

• Last Update Posted (Actual): January 31, 2018
• Last Update Submitted That Met QC Criteria: January 29, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: drug resistance; gene polymorphism
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; 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: Pro00003846

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Plan to share data to be determined.