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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Dabigatran then dabigatran and clarithromycin; Drug: Clarithromycin and dabigatran then dabigatran	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	10 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Single (Outcomes Assessor)
Official Title:	Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin
Study Start Date :	June 2011
Actual Primary Completion Date :	December 2011
Actual Study Completion Date :	December 2011

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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: Dabigatran (Pradaxa) 75 mg; Clarithromycin (Zeclar) 500 mg

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Pharmacodynamic parameters [ Time Frame: At Day 4 and Day 11 ]
   Measures activated Partial Thromboplastin Time (aPTT)and measures ECarin Time (ECT),
2. Genotyping [ Time Frame: At Day 1 ]
   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

Eligibility Criteria

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years to 35 Years (Adult)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Centre Hospitalier Universitaire de Saint Etienne

Groupe de Recherche sur la Thrombose

Investigators

Principal Investigator:	Patrick MISMETTI, MD PhD	CHU de Saint-Etienne
Study Chair:	Xavier DELAVENNE, Pharmacist	CHU de Saint-Etienne

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Centre Hospitalier Universitaire de Saint Etienne
ClinicalTrials.gov Identifier:	NCT01385683 History of Changes
Other Study ID Numbers:	1008073; 2010-024047-33 ( EudraCT Number )
First Posted:	June 30, 2011
Last Update Posted:	March 22, 2012
Last Verified:	March 2012

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:

Healthy volunteer; Pharmacokinetic; pharmacodynamic; Polymorphism, Genetic

Additional relevant MeSH terms:

Clarithromycin; Dabigatran; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action	Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Anticoagulants