Impact of Citalopharm and Fluvoxamine on Platelet Response to Clopidogrel

Impact of Citalopharm and Fluvoxamine on Platelet Response to Clopidogrel, a Randomized, Double-blind, Crossover Trial

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.

Study Overview

• Status: Completed
• Conditions: Drug Interactions Between Clopidogrel and Serotonin Reuptake Inhibitors
• Intervention / Treatment: Drug: fluvoxamine; Drug: citalopharm

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy volunteers

Exclusion Criteria:

• Bleeding tendency
• Hypersensitivity to study drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: fluvoxamine	Drug: fluvoxamine; Fluvoxamine 100mg daily, 7 days
Active Comparator: citalopharm	Drug: citalopharm; Citalopharm 20mg daily, 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet reactivity in response to clopidogrel	We will assess response to clopidogrel by two methods: 1. % change in platelet aggregation using light transmission aggregometry with ADP as agonist. 2. % of change in VASP phosphorylation - measure of activation of the platelet P2Y12 receptor (targeted by clopidogrel). The response clopidogrel will be measured after administration of clopidogrel and after co-administration of clopidogrel and each of the study drugs (fluvoxamine and citalophram). Statistical analysis will be performed to assess differences in platelet function between the different drug treatments.	12 months

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization

Publications and helpful links

General Publications

• Hirsh-Rokach B, Spectre G, Shai E, Lotan A, Ritter A, Al-Aieshy F, Malmstrom RE, Varon D, Alcalai R. Differential impact of selective serotonin reuptake inhibitors on platelet response to clopidogrel: a randomized, double-blind, crossover trial. Pharmacotherapy. 2015 Feb;35(2):140-7. doi: 10.1002/phar.1542.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: July 14, 2011
• First Submitted That Met QC Criteria: July 17, 2011
• First Posted (Estimate): July 19, 2011

Study Record Updates

• Last Update Posted (Estimate): January 29, 2013
• Last Update Submitted That Met QC Criteria: January 26, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluvoxamine
• Other Study ID Numbers: 0255-HMO-CTIL