Impact of Citalopharm and Fluvoxamine on Platelet Response to Clopidogrel
Condition: Drug Interactions Between Clopidogrel and Serotonin Reuptake Inhibitors
Study type: Interventional
Phase: Phase 1

Summary: 
      Clopidogrel is a platelets inhibitor that is widely used particularly during and after acute
      coronary events and coronary interventions. Several studies have shown that some patients are
      resistant to clopidogrel. The resistance mechanism is not entirely clear, but at least in
      part it is related to interactions between medications. Clopidogrel is a pro-drug converted
      in vivo to its active metabolite by CYP2C19 and CYP3A in the liver. Consequently drugs that
      inhibit the CYP2C19 can affect the production of the active metabolite and cause "clopidogrel
      resistance". Therefore the FDA has recently published a "safety alert" which recommends
      avoiding cross treatment with clopidogrel and drugs that are expected to inhibit CYP2C19
      (including omeprazole, fluvoxamine, cimetidine, fluconazole and others). Nevertheless there
      no clear evidence in the literature for clinical relevance of such interactions.

      Selective serotonin reuptake inhibitors (SSRIs) are group of antidepressant drugs that are
      widely used for treatment of depression and anxiety. SSRIs are considered to be very safe
      with favorable side effect profile, hence many patient after coronary events who suffers from
      behavioral and emotional disturbances are treated with those drugs. However there are several
      reports that SSRIs can inhibit platelet function and increase bleeding tendency particularly
      in concomitant administration with aspirin. The proposed mechanism is blocking of platelets
      serotonin reuptake that result in platelet dysfunction.

      Fluvoxamine - is a member in the SSRI family and a potent inhibitor of the CYP2C19.
      Theoretically fluvoxamine should have two conflicting effects on the response to clopidogrel.
      Pharmacokinetically it is expected to decrease the clopidogrel responsiveness due to
      inhibition of CYP2C19 and reduction in the production of the active metabolite. On the other
      hand "pharmacodynamically" fluvoxamine may directly inhibit platelet aggregation due its
      effect on serotonin reuptake, thus increasing the effect of clopidogrel. Other SSRIs that do
      not interact with the CYP2C19 such as citalophram are expected to have only pharmocodynamic
      effect on platelet aggregation.

      Although both clopidogrel and SSRIs are widely used in the last decade and concomitant
      treatment is quite common, no data is available about in influence of the interaction between
      those drugs on platelet function and on clinical events. The net effect of fluvoxamine and
      other SSRIs on platelet function in the presence of clopidogrel is not known.

      The aim of the investigators study is to assess the effect of two SSRIs fluvoxamine and
      citalophram on platelet aggregation and to test the effect of these drugs on the laboratory
      response to clopidogrel, in healthy individuals.

      Study design: randomized, double blinded, controlled crossover trial. Primary study end
      point: Change in % platelet aggregation and VASP phosphorylation after treatment with
      clopidogrel + fluvoxamine or clopidogrel + citalophram as compared to each drug alone.
    


Intervention name(s): fluvoxamine; citalopharm
Intervention type(s): Drug; Drug
Intervention description(s): Fluvoxamine 100mg daily, 7 days; Citalopharm 20mg daily, 7 days
Intervention MeSH terms: Fluvoxamine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment