Investigation of Drug-drug Interaction Between Clopidogrel and Fluoxetine

Study Overview
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Brief Summary
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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.

Official Title
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Investigation of Drug-drug Interaction Between Clopidogrel and Fluoxetine

Conditions
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Healthy

Intervention / Treatment
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* Drug: Clopidogrel then fluoxetine+clopidogrel
* Drug: Fluoxetine+clopidogrel then clopidogrel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Clopidogrel then fluoxetine+clopidogrel | Drug: Clopidogrel then fluoxetine+clopidogrel<br>* 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<br>|
| Active Comparator: 2<br>Fluoxetine+clopidogrel then clopidogrel | Drug: Fluoxetine+clopidogrel then clopidogrel<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteer, Pharmacokinetic, pharmacodynamic, Polymorphism, Genetic