Bioavailability of Different Applications of Dabigatran in Healthy Volunteers

Study Overview
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Brief Summary
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To determine the relative bioavailability of 150 mg of dabigatran etexilate as pellets on food and of 150 mg of dabigatran etexilate as powder resolved in reconstitution solution, both with 150 mg of dabigatran etexilate as capsule in healthy volunteers

Official Title
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Relative Bioavailability of Dabigatran After Administration of Different Application Forms of a Single Oral Dose of 150 mg Dabigatran Etexilate (Capsule, Powder for Reconstitution Into Solution, Pellets on Food) in Healthy Male and Female Volunteers (an Open-label, Randomised, Three-way Crossover, Clinical Phase I Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran etexilate pellets
* Drug: Dabigatran etexilate powder
* Drug: Dabigatran etexilate capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests Age ≥18 and age ≤50 years BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index) Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation Exclusion Criteria: Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract (except appendectomy) 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 relevant allergy/hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs which could reasonably influence the results of the trial (especially unspecific inducing agents like St. John´s wort (Hypericum perforatum) or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within two months prior to administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range that was of clinical relevance Inability to comply with dietary regimen of trial site A marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for Torsade de Pointes (e.g. heart failure, hypokalemia, family history of Long QT Syndrome) For female subjects: Positive pregnancy test, pregnancy or planning to become pregnant during the study or within 1 month after study completion No adequate contraception during the study and until 1 month after study completion, i.e. not any of the following: implants, injectables, combined oral contraceptives, intrauterine device (IUD), 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 to be asked to use an additional barrier method (e.g. condom, diaphragm with spermicide) Lactation Intake of medication, which influences the blood clotting, i.e. acetylsalicylic acid, oral vitamin K antagonists etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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 pellets<br> | Drug: Dabigatran etexilate pellets<br> <br> |
| Experimental: Dabigatran etexilate powder<br> | Drug: Dabigatran etexilate powder<br> <br> |
| Active Comparator: Dabigatran etexilate capsule<br> | Drug: Dabigatran etexilate capsule<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-inf for Total Dabigatran | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| AUC0-inf for Free Dabigatran | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Cmax for Total Dabigatran | Maximum measured concentration of the analyte in plasma (Cmax) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Cmax for Free Dabigatran | Maximum measured concentration of the analyte in plasma (Cmax) for free dabigatran | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-tz for Total Dabigatran | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| AUC0-tz for Free Dabigatran | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Tmax for Total Dabigatran | Time from dosing to the maximum concentration of the analyte in plasma (tmax) for total dabigatran | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Tmax for Free Dabigatran | Time from dosing to the maximum concentration of the analyte in plasma (tmax) for free dabigatran | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| λz for Total Dabigatran | Terminal rate constant in plasma (λz) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| λz for Free Dabigatran |  | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| t1/2 for Total Dabigatran | Terminal half-life of the analyte in plasma (t1/2) for total dabigatran | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| t1/2 for Free Dabigatran | Terminal half-life of the analyte in plasma (t1/2) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| MRTpo for Total Dabigatran | Mean residence time of the analyte in the body after po administration (MRTpo) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| MRTpo for Free Dabigatran | Mean residence time of the analyte in the body after po administration (MRTpo) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| CL/F for Total Dabigatran | Apparent clearance of the analyte in plasma following extravascular administration (CL/F) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| CL/F for Free Dabigatran | Apparent clearance of the analyte in plasma following extravascular administration (CL/F) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Vz/F for Total Dabigatran | Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) for total dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Vz/F for Free Dabigatran | Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) for free dabigatran. | -0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | 
| Percentage of Participants With Findings in Physical Examination, Vital Signs , Pulse Rate (PR)), 12-lead ECG, Clinical Laboratory Tests. | Percentage of participants with findings in Physical examination, Vital signs (blood pressure (BP), pulse rate (PR)), 12-lead ECG (electrocardiogram), Clinical laboratory tests (haematology, clinical chemistry and urinalysis). Relevant findings or worsening of baseline conditions were reported as Adverse events. There were no clinically relevant finding reported for Physical examination, Vital signs (blood pressure, pulse rate), 12-lead ECG and Clinical laboratory tests. | From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days. | 
| Percentage of Participants With Drug-related Adverse Events | Percentage of participants with investigator defined drug-releated Adverse events. | From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days. | 
| Assessment of Tolerability by Investigator. | Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory and bad. | From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days. |