Investigation of Drug-drug Interaction Between Clopidogrel and Fluoxetine

Centre Hospitalier Universitaire de Saint Etienne10 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

SINGLE

Enrollment

Conditions

Healthy

Interventions

Eligibility

Sex: MALEMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Platelet aggregation inhibition measured by optical aggregometry in presence of adenosine diphosphate (ADP) 20 μmol/L and 5 μmol/L.

Time frame: Before first fluoxetin taking, during clopidogrel taking

Secondary Outcomes

Level of phosphorylated VASP (vasodilator- stimulated phosphoprotein), a good index of P2Y12 activity (platelet receptor of clopidogrel) and P-selectin by flow cytometry.

Time frame: Before first Fluoxetine taking and during Clopidogrel taking

Determination of clopidogrel and its metabolites in plasma by LC/MS-MS method

Time frame: During clopidogrel taking