Relative Bioavailability and Pharmacodynamics of Dabigatran With Enoxaparin in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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To investigate the relative bioavailability and the pharmacodynamics of dabigatran after switching from enoxaparin to dabigatran etexilate as compared to dabigatran etexilate alone

Official Title
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Relative Bioavailability and Pharmacodynamics of Dabigatran After a Single Dose of 220 mg Dabigatran Etexilate and After 40 mg Enoxaparin s.c. for 3 Days Followed by a Single Dose of 220 mg Dabigatran Etexilate in Healthy Male and Female Volunteers (an Open-label, Randomised, Single and Multiple Dose, Two Way Crossover Phase I Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Enoxaparin prefilled syringes
* Drug: Dabigatran etexilate capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects were healthy males and females based upon a complete medical history, including a physical examination, vital signs (blood pressure, pulse rate), 12-lead ECG, and clinical laboratory tests Age ≥18 to ≤55 years Body mass index (BMI) ≥18.5 to ≤29.9 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation Exclusion Criteria: Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorders Relevant surgery of gastrointestinal tract History of any bleeding disorder or acute blood coagulation defect Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of allergy/hypersensitivity (including drug allergy) which was deemed relevant to the trial as judged by the investigator Intake of any medication within 2 weeks of first dosing, especially intake of medication, which influences blood clotting, i.e. acetylsalicylic acid, cumarin etc. Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 4 weeks prior to administration or during the trial Alcohol abuse (more than 60 g/day for males and more than 20 g/day for females) Drug abuse Intake of grapefruit, grapefruit juice, or products containing grapefruit juice, Seville oranges, garlic supplements, or St. John's wort within 5 days of first dosing Participation in another trial with an investigational drug within 2 months prior to trial drug administration or during the trial Blood donation (more than 100 mL within 4 weeks prior to trial drug administration or during the trial) Excessive physical activities (within 1 week prior to trial drug administration or during the trial) Any laboratory value outside the reference range that was of clinical relevance Inability to comply with dietary regimen of study centre Smoker (>10 cigarettes or >3 cigars or >3 pipes/day) Inability to refrain from smoking on trial days For female subjects: Pregnancy / positive pregnancy test, or planning to become pregnant during the study or within 1 month after study completion No adequate contraception during the study and within 1 month after study completion such as implants, injectables, combined oral contraceptives, intrauterine device, sexual abstinence (for at least 1 month prior to enrolment), vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who did not have a vasectomised partner, were not sexually abstinent or surgically sterile, were asked to additionally use a barrier contraception method (e.g. condom, diaphragm with spermicide) Lactation period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate capsules after enoxaparin ampoules<br> | Drug: Enoxaparin prefilled syringes<br> <br> Drug: Dabigatran etexilate capsules<br> <br> |
| Active Comparator: Dabigatran etexilate capsules without enoxaparin<br> | Drug: Dabigatran etexilate capsules<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) of dabigatran |  | Up to 48 hours after drug administration | 
| Maximum measured concentration of the analyte in plasma (Cmax ) of dabigatran |  | Up to 48 hours after drug administration | 
| Area under the effect-time curve of the analyte in plasma over the time interval from 0 to 48 h after administration (AUEC0-48) after dabigatran alone and after dabigatran following enoxaparin administration |  | Up to 48 hours after drug administration | 
| Maximum effect ratio to baseline (ERmax) after dabigatran alone and after dabigatran following enoxaparin administration |  | Baseline and up to 48 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) of dabigatran |  | Up to 48 hours after drug administration | 
| Time from dosing to the maximum concentration of the analyte in plasma (tmax) of dabigatran |  | Up to 48 hours after drug administration | 
| Terminal rate constant in plasma (λz) of dabigatran |  | Up to 48 hours after drug administration | 
| Terminal half-life of the analyte in plasma (t1/2) of dabigatran |  | Up to 48 hours after drug administration | 
| Mean residence time of the analyte in the body after oral administration (MRTpo) of dabigatran |  | Up to 48 hours after drug administration | 
| Apparent clearance of the analyte in plasma after extravascular administration (CL/F) of dabigatran |  | Up to 48 hours after drug administration | 
| Apparent volume of distribution during the terminal phase λz following an extravascular administration (Vz/F) of dabigatran |  | Up to 48 hours after drug administration | 
| Anti-FIIa activity for Dabigatran etexilate |  | Up to 48 hours after drug administration | 
| Anti-FXa/anti-FIIa activity for Enoxaparin |  | Up to 48 hours after drug administration | 
| Activated partial thromboplastin time (aPTT) for Dabigatran etexilate |  | Up to 48 hours after drug administration | 
| Ecarin clotting time (ECT) for Dabigatran etexilate |  | Up to 48 hours after drug administration | 
| Thrombin time (TT) for Dabigatran etexilate |  | Up to 48 hours after drug administration | 
| Change in vital signs (blood pressure, pulse rate) |  | up to day 61 | 
| Change in 12-lead electrocardiogram (ECG) |  | up to day 61 | 
| Change in clinical laboratory tests |  | up to day 61 | 
| Occurrence of adverse events |  | Up to day 61 | 
| Assessment of global tolerability by investigator on a four point scale (good, satisfactory, not satisfactory, bad) |  | Day 61 | 
| Assessment of local tolerability by investigator on a four point scale (good, satisfactory, not satisfactory, bad) |  | day 3 of enoxaparin administration |