Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin

Study Overview
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Brief Summary
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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.

Official Title
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Investigation Drug-drug Interaction Between Dabigatran and Clarithromycin

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran then dabigatran and clarithromycin
* Drug: Clarithromycin and dabigatran then dabigatran


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Dabigatran then dabigatran and clarithromycin | Drug: Dabigatran then dabigatran and clarithromycin<br>* 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)<br>* Other names: Clarithromycin (Zeclar) 500 mg;|
| Active Comparator: Arm B<br>Clarithromycin and dabigatran and dabigatran | Drug: Clarithromycin and dabigatran then dabigatran<br>* 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.<br>* Other names: Clarithromycin (Zeclar) 500 mg;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteer, Pharmacokinetic, pharmacodynamic, Polymorphism, Genetic