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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: CLOPIDOGREL; Drug: placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence clopidogrel 300/75 mg - 600/150 mg; 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; Pharmaceutical form: tablets Route of administration: oral; Other Names: SR25990; Drug: placebo; Pharmaceutical form: matching tablets Route of administration: oral
Experimental: Sequence clopidogrel 600/150 mg - 300/75 mg; 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; Pharmaceutical form: tablets Route of administration: oral; Other Names: SR25990; Drug: placebo; Pharmaceutical form: matching tablets Route of administration: oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Bristol-Myers Squibb
• Investigators: Study Chair: International Clinical Development Study Director, Sanofi

Publications and helpful links

General Publications

• Simon T, Bhatt DL, Bergougnan L, Farenc C, Pearson K, Perrin L, Vicaut E, Lacreta F, Hurbin F, Dubar M. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther. 2011 Aug;90(2):287-95. doi: 10.1038/clpt.2011.127. Epub 2011 Jun 29.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): August 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: May 12, 2010
• First Submitted That Met QC Criteria: May 13, 2010
• First Posted (Estimate): May 14, 2010

Study Record Updates

• Last Update Posted (Estimate): December 15, 2011
• Last Update Submitted That Met QC Criteria: December 14, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: healthy subjects
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: PKD11147; 2009-010105-37 (EudraCT Number)