Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin (IMAGINE)

Dabigatran (Pradaxa ®) is a new oral anticoagulant. It is used to prevent venous thromboembolism in orthopedic surgery and has recently demonstrated efficacy and safety at least as good as anticoagulants in the prevention of thromboembolism in atrial fibrillation and the treatment of venous thromboembolism. It is administered with fixed dose and does not require laboratory monitoring because of the low inter and intra individual pharmacokinetic (PK) and pharmacodynamics (PD) of dabigatran. However, the bioavailability of dabigatran is very low (6.5%) and is controlled by an efflux protein, P-GP. This molecule has a genetic polymorphism. The inhibition of this protein can cause a significant increase in intestinal absorption of dabigatran and expose patients to a risk of bleeding by overdose. Two major drug interactions have been identified : quinidine (cons-indication) and amiodarone (precautions). It is likely that other interactions exist and can be clinically significant in patients not selected such as testing. The development of tools to study the influence of P-GP on the PK and PD of dabigatran is therefore interesting. As the P-GP has a genetic polymorphism, the study of the latter is an important element in the detection of drug interactions. In this sense, clarithromycin, a potent inhibitor of P-GP is a good model to evaluate the primary mechanism of drug interaction of dabigatran and optimize the experimental design of studies to be conducted.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dabigatran then dabigatran and clarithromycin; Drug: Clarithromycin and dabigatran then dabigatran

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

Contacts and Locations

Study Locations

• France
  • Saint-Etienne, France, 42055
    • Service de Medecine et Therapeutique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• affiliated or beneficiary of a social security category
• having signed the inform consent form
• having signed the genetic consent form
• weight between 60 and 85 kg
• normal clinical exam
• normal biological exam

Exclusion Criteria:

• contra-indication to dabigatran
• contra-indication to clarithromycin
• previous history of psychiatric disease, or antidepressant treatment, or convulsion, or hemorrhagic disease
• smoker
• peptic ulcer
• severe liver disease
• severe kidney failure
• previous surgery within one month

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: Arm A; Dabigatran then dabigatran and clarithromycin	Drug: Dabigatran then dabigatran and clarithromycin; D4 : dabigatran 300 mg (4 tablets) one time. D8 to D10 : Clarithromycin 500mg (1 tablet) twice daily. D11 : Clarithromycin 500mg (1 tablet) + 300mg dabigatran (4 tablets); Other Names: Dabigatran (Pradaxa)75 mg; Clarithromycin (Zeclar) 500 mg
Active Comparator: Arm B; Clarithromycin and dabigatran and dabigatran	Drug: Clarithromycin and dabigatran then dabigatran; D1 to D3 : Clarithromycin 500mg (1 tablet) twice daily. D4 : Clarithromycin 500mg (1 tablet) + 300mg dabigatran (4 tablets). D11 : dabigatran 300 mg (4 tablets) one time.; Other Names: Clarithromycin (Zeclar) 500 mg; Dabigatran (Pradaxa) 75 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of dabigatran and its metabolites in plasma by LC/MS-MS method	Calculating the area under the curve (AUC) from plasma concentrations of dabigatran versus time by the trapezoidal method. Determination of maximum concentration (Cmax)	At Day 4 and Day 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic parameters	Measures activated Partial Thromboplastin Time (aPTT)and measures ECarin Time (ECT),	At Day 4 and Day 11
Genotyping	Genotyping of MDR-1 (gene for P-GP): C3435T SNP of exon 26, SNP G2677T / A of exon 21 and C1236T SNP of exon 12	At Day 1

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Groupe de Recherche sur la Thrombose
• Investigators: Study Chair: Xavier DELAVENNE, Pharmacist, CHU de Saint-Etienne

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: June 27, 2011
• First Submitted That Met QC Criteria: June 29, 2011
• First Posted (Estimate): June 30, 2011

Study Record Updates

• Last Update Posted (Estimate): March 22, 2012
• Last Update Submitted That Met QC Criteria: March 21, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Pharmacokinetic; pharmacodynamic; Healthy volunteer; Polymorphism, Genetic
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran; Clarithromycin
• Other Study ID Numbers: 1008073; 2010-024047-33 (EudraCT Number)