Pharmacodynamic and Pharmacokinetic Study of 2 Different Dose Regimen of Clopidogrel in CYP2C19 Genotyped Healthy Subjects - Full Text View

Purpose

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

Condition	Intervention	Phase
Healthy	Drug: CLOPIDOGREL Drug: placebo	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Basic Science
Official Title:	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

Resource links provided by NLM:

Drug Information available for: Clopidogrel bisulfate

U.S. FDA Resources

Further study details as provided by Sanofi:

Primary Outcome Measures:

Maximum platelet aggregation intensity (MAI) induced by Adenosine diphosphate (ADP) 5 µM after 5 days treatment [ Time Frame: Day 5 of each period ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Maximum platelet aggregation intensity (MAI) induced by ADP 20 µM after 5 days treatment [ Time Frame: Day 5 of each period ] [ Designated as safety issue: No ]
Platelet reactivity index -Vasodilator-stimulated phosphoprotein test (PRI-VASP) after 5 days treatment [ Time Frame: Day 5 of each period ] [ Designated as safety issue: No ]
Clopidogrel active metabolite pharmacokinetic parameters (Cmax, tmax, AUC0-24, AUClast) after 5 days treatment [ Time Frame: Up to 24 hours postdose on Day 5 for each period ] [ Designated as safety issue: No ]

Enrollment:	40
Study Start Date:	April 2009
Study Completion Date:	August 2009
Primary Completion Date:	August 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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 Name: SR25990 Drug: placebo Pharmaceutical form: matching tablets Route of administration: oral

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

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01123824

Locations

Germany
Sanofi-Aventis Administrative Office
Berlin, Germany

Sponsors and Collaborators

Sanofi

Bristol-Myers Squibb

Investigators

Study Chair:

International Clinical Development Study Director

Sanofi

More Information

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. Epub 2011 Jun 29.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT01123824 History of Changes
Other Study ID Numbers:	PKD11147, 2009-010105-37
Study First Received:	May 12, 2010
Last Updated:	December 14, 2011
Health Authority:	United States: Food and Drug Administration Germany: Paul-Ehrlich-Institut

Keywords provided by Sanofi:

healthy subjects

Additional relevant MeSH terms:

Clopidogrel
Ticlopidine
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists

Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on May 23, 2013