Clinical Trial to Evaluate the Influence of Genotype on the Pharmacokinetics/Pharmacodynamics of Clopidogrel

Clinical Trial to Evaluate the Influence of Genotype of Drug Metabolizing Enzyme or Transporter and Drug-drug Interactions on the Pharmacokinetics/Pharmacodynamics of Clopidogrel in Healthy Volunteers

This study has an open-label, five-period, single-sequence design. The purpose of this study is as follows;

1. Primary

   • To evaluate the influence of genotype of drug metabolizing enzyme or transporter on the pharmacokinetics/pharmacodynamics of clopidogrel
   • To evaluate the influence of aspirin on the pharmacokinetics/pharmacodynamics of clopidogrel

2. Secondary

   • To explore the representative biomarkers for the variable pharmacokinetics/pharmacodynamics of clopidogrel
   • To evaluate the influence of genotype of drug metabolizing enzyme or transporter on the drug-drug interactions between aspirin and clopidogrel
   • To explore the representative biomarkers for the drug-drug interactions between aspirin and clopidogrel

Study Overview

• Status: Completed
• Conditions: Influence of Genotype of Drug Metabolizing Enzyme or Transporter on the Pharmacokinetics/Pharmacodynamics of Clopidogrel; Influence of Aspirin on the Pharmacokinetics/Pharmacodynamics of Clopidogrel
• Intervention / Treatment: Drug: Clopidogrel+Aspirin

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital Clinical Trials Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 1. Healthy male subjects aged 20 - 45 years.
• 2. A body weight in the range of 50 kg (inclusive) - 90 kg (exclusive) and a body mass index (BMI) in the range 18.5 kg/m2 (inclusive) - 27 kg/m2 (inclusive).
• 3. Sufficient ability to understand the nature of the study and any hazards of participating in it. Provide written informed consent after being fully. informed about the study procedures.

Exclusion Criteria:

• 1. Presence or history of hypersensitivity or allergic reactions to drugs including investigational product (clopidogrel or aspirin)
• 2. Clinically relevant abnormal medical history that could interfere with the objectives of the study.
• 3. A subject with history of gastrointestinal disease or surgery (except simple appendectomy or repair of hernia), which can influence the absorption of the study drug.
• 4. A subject whose lab test results are as follows; Platelet count or PT, aPTT < 0.9 x lower limit of reference range of > 1.1 x upper limit of reference range.
• 5. A subject whose SBP is over 160 mmHg or below 90 mmHg and DBP is over 100 mmHg or below 50 mmHg.
• 6. Presence or history of drug abuse or positive result in urine drug screening test.
• 7. Participation in other clinical trial within 2 months before first dose.
• 8. Use of CYP inducer (ex. rifampin) within 4 weeks before first dose.
• 9. Use of a prescription medicine, herbal medicine within 2 weeks or over-the-counter medication or vitamin substances within 1 week before first dose.
• 10.Use of grapefruit juice within 1 week before first dose.
• 11. Blood donation during 2 months or apheresis during 1 month before the study.
• 12. Use of alcohol over 21 units/weeks
• 13. Smoking of more than 10 cigarettes/days within 3 months before first dose.
• 14. Subject judged not eligible for study participation by investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clopidogrel+Aspirin; Clopidogrel on Day 1, Aspirin on Day 2 - Day 14, Clopidogrel + Aspirin Day 15, Aspirin on Day 16 - Day 28, Clopidogrel + Aspirin Day 29	Drug: Clopidogrel+Aspirin; Clopidogrel 75 mg, Aspirin 100 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of Clopidogrel	Plasma concentration of clopidogrel and active metabolite of clopidogrel	Predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h postdose on Day 1, Day 15 and Day 29
Pharmacodynamics of clopidogrel	Relative inhibition of platelet aggregation by aggregometer or VerifyNow	Predose and 4, 24 h postdose on Day 1, Day 15 and Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mRNA/microRNA/endogenous metabolite	mRNA of PON1 and CYP2C19, CYP3A5, MDR1 microRNA endogenous metabolite	predose on Day 1, Day 8, Day 15, Day 22 and Day 29

Collaborators and Investigators

• Sponsor: Seoul National University Hospital

Publications and helpful links

General Publications

• Oh J, Shin D, Lim KS, Lee S, Jung KH, Chu K, Hong KS, Shin KH, Cho JY, Yoon SH, Ji SC, Yu KS, Lee H, Jang IJ. Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity. Clin Pharmacol Ther. 2014 Jun;95(6):608-16. doi: 10.1038/clpt.2014.49. Epub 2014 Feb 24.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: January 1, 2012
• First Submitted That Met QC Criteria: January 3, 2012
• First Posted (Estimate): January 4, 2012

Study Record Updates

• Last Update Posted (Estimate): June 19, 2012
• Last Update Submitted That Met QC Criteria: June 18, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Pharmacogenomics; Aspirin,; Clopidogrel,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Clopidogrel
• Other Study ID Numbers: PGX_Clopidogrel_001