Investigation of Drug-drug Interaction Between Clopidogrel and Fluoxetine (PLATINE)

Clopidogrel is a platelet aggregation inhibitor witch prevents thrombotic events in patients with atherosclerotic vascular disease. To date, 4 to 30 % of patients are considered as poor, low or non-responder to this therapeutic. However, drug-drug interactions may lead to decrease the clopidogrel responsiveness. Many arguments are in support to a drug-drug interaction between clopidogrel and fluoxetine (selective serotonin reuptake inhibitor). On the pharmacokinetic level, fluoxetine inhibits the cytochroms involved in the production of clopidogrel active metabolite. On the pharmacodynamic level fluoxetine could increase the risk of hemorrhage by inhibiting the serotonin platelet reuptake and thus enhance the antiplatelet effect of clopidogrel.

The purpose of this study is to investigate the influence of fluoxetine on pharmacokinetic and pharmacodynamic of clopidogrel.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Clopidogrel then fluoxetine+clopidogrel; Drug: Fluoxetine+clopidogrel then clopidogrel

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Saint-Etienne, France, 42055
    • Service de Medecin et Therapeutique, Unite de Recherche Clinique Groupe de Recherche sur la Thrombose (EA3065)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Signed an informed consent
• Body mass: 60 to 85 Kg
• Platelet count: 180 to 350 G/L
• % platelet aggregation > 70%
• Subjects are to be in good health as determined by a medical history, physical examination including vital signs, and clinical laboratory test results including liver function, renal and full blood count

Exclusion Criteria:

• Subject with an history of seizure disorder
• Subject with a known allergy fluoxetine or clopidogrel
• Cigarette smoking
• Subject with a history of hemorrhagic disease
• Peptic ulcer
• Psychiatric disorders
• Participation in another clinical or device trial within the three previous months
• Subject who is currently taking medications
• Subject who is currently taking medications for depression
• Subject with an history of depression (MADRS score < 15)
• Hepatic insufficiency

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Clopidogrel then fluoxetine+clopidogrel	Drug: Clopidogrel then fluoxetine+clopidogrel; D1 : clopidogrel (Plavix) 600mg (8 tablets) one time D45 to D48 : Fluoxetine (Fluoxetine EG 20mg) 20mg (1 tablet) per day D49 : 20mg Fluoxetine + 600mg Clopidogrel
Active Comparator: 2; Fluoxetine+clopidogrel then clopidogrel	Drug: Fluoxetine+clopidogrel then clopidogrel; D1 to D4 : Fluoxetine (Fluoxetine EG 20mg) 20mg (1 tablet) per day D5: 20mg Fluoxetine + Clopidogrel (Plavix) 600mg (8 tablets) one time D49 : Clopidogrel 600mg one time

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Platelet aggregation inhibition measured by optical aggregometry in presence of adenosine diphosphate (ADP) 20 μmol/L and 5 μmol/L.	Before first fluoxetin taking, during clopidogrel taking

Secondary Outcome Measures

Outcome Measure	Time Frame
Level of phosphorylated VASP (vasodilator- stimulated phosphoprotein), a good index of P2Y12 activity (platelet receptor of clopidogrel) and P-selectin by flow cytometry.	Before first Fluoxetine taking and during Clopidogrel taking
Determination of clopidogrel and its metabolites in plasma by LC/MS-MS method	During clopidogrel taking

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Investigators: Principal Investigator: PIERRE GARNIER, MD, CHU DE SAINT-ETIENNE

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): May 1, 2009
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: August 8, 2008
• First Submitted That Met QC Criteria: August 8, 2008
• First Posted (Estimate): August 11, 2008

Study Record Updates

• Last Update Posted (Estimate): March 25, 2013
• Last Update Submitted That Met QC Criteria: March 22, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetic; pharmacodynamic; Healthy volunteer; Polymorphism, Genetic
• Additional Relevant MeSH Terms: 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; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Clopidogrel; Fluoxetine
• Other Study ID Numbers: 0801068; 2008-004395-46