Pharmacodynamic and Pharmacokinetic Study of 2 Different Dose Regimen of Clopidogrel in CYP2C19 Genotyped Healthy Subjects

Study Overview
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Brief Summary
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Primary Objective: Investigate the possible role of the CYP2C19 genotype in Adenosine diphosphate (ADP)-induced platelet aggregation after administration of a standard dose regimen of clopidogrel (300 mg loading dose followed by 75 mg/day for 4 days) in healthy male and female subjects Secondary Objectives: Assess the pharmacodynamic activity of a higher dose regimen of clopidogrel (600 mg loading dose followed by 150 mg/day for 4 days) Compare the pharmacokinetic profiles of clopidogrel active metabolite between the selected groups of genotyped subjects and the 2 dose regimen

Detailed Description
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The total study duration per subject is 10-12 weeks broken down as follows: Screening: 2 to 40 days before the first dosing Period 1: 7 days including 5 days treatment Washout: At least 14 days after the last dosing Period 2: 7 days including 5 days treatment End of study: 7 to 10 days after the last dosing

Official Title
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A Randomized, Double-blind, Double-dummy, Two Period, Two Treatment Cross-over Pharmacodynamic and Pharmacokinetic Study of Clopidogrel Given as 5-day Repeated Oral Doses (300 mg Loading Dose Followed by 75 mg/Day and 600 mg Loading Dose Followed by 150 mg/Day) in 4 Different Groups of CYP2C19 Genotyped Healthy Male and Female Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: CLOPIDOGREL
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy subject in good health, as determined by a medical history, physical examination including vital signs and clinical laboratory tests: with a body weight between 45 kg and 95 kg if male, between 40 kg and 85 kg if female, and with a Body Mass Index (BMI) between 18 and 30 kg/m² classified into one of the 4 groups of metabolizers according to his/her CYP2C19 genotype: Ultrarapid Metabolizers (UMs, CYP2C19*1/*17 and CYP2C19*17/*17) homozygous Extensive Metabolizers (homoEMs, CYP2C19*1/*1) heterozygous Extensive Metabolizers (heteroEMs, CYP2C19*1/*2 and CYP2C19*1/*3) Poor Metabolizers (PMs, CYP2C19*2/*2 and CYP2C19*2/*3) Exclusion criteria: Evidence of inherited disorder of coagulation/hemostasis functions Subject smoking more than 10 cigarettes or equivalent per day Unability to abstain from intake of any drug affecting hemostasis throughout the whole study duration The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence clopidogrel 300/75 mg - 600/150 mg<br>Period 1: Day 1: clopidogrel, 300 mg loading dose + placebo Day 2 to Day 5: clopidogrel, 75 mg + placebo, once daily Period 2: Day 1: clopidogrel, 600 mg loading dose Day 2 to Day 5: clopidogrel, 150 mg, once daily Each intake is at around 8:00 AM fasted for at least 10 hours | Drug: CLOPIDOGREL<br>* Pharmaceutical form: tablets Route of administration: oral<br>* Other names: SR25990;Drug: placebo<br>* Pharmaceutical form: matching tablets Route of administration: oral<br>|
| Experimental: Sequence clopidogrel 600/150 mg - 300/75 mg<br>Period 1: Day 1: clopidogrel, 600 mg loading dose Day 2 to Day 5: clopidogrel, 150 mg, once daily Period 2: Day 1: clopidogrel, 300 mg loading dose + placebo Day 2 to Day 5: clopidogrel, 75 mg + placebo, once daily Each intake is at around 8:00 AM fasted for at least 10 hours | Drug: CLOPIDOGREL<br>* Pharmaceutical form: tablets Route of administration: oral<br>* Other names: SR25990;Drug: placebo<br>* Pharmaceutical form: matching tablets Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum platelet aggregation intensity (MAI) induced by Adenosine diphosphate (ADP) 5 µM after 5 days treatment |  | Day 5 of each period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum platelet aggregation intensity (MAI) induced by ADP 20 µM after 5 days treatment |  | Day 5 of each period | 
| Platelet reactivity index -Vasodilator-stimulated phosphoprotein test (PRI-VASP) after 5 days treatment |  | Day 5 of each period | 
| Clopidogrel active metabolite pharmacokinetic parameters (Cmax, tmax, AUC0-24, AUClast) after 5 days treatment |  | Up to 24 hours postdose on Day 5 for each period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy subjects