Bioequivalence of Two Different Generations of Drug Product of Dabigatran Etexilate Following Oral Administration in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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The objective was to demonstrate the bioequivalence of capsules made from 2 different drug product batches. The reference batch was representative of the current commercial drug product and of the pivotal Phase III batches. The test batch was the drug product batch intended for future commercial use.

Official Title
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Bioequivalence of Two Different Generations of Drug Product of 150 mg Dabigatran Etexilate Following Oral Administration in Healthy Male and Female Volunteers (Double-blind, Randomised, Single Dose, Replicate Design in a Two Treatments, Four Periods Crossover Phase I Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran etexilate generation I
* Drug: Dabigatran etexilate generation II


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 (blood pressure, pulse rate), 12-lead electrocardiogram, clinical laboratory tests Age ≥60 and ≤85 years Body mass index (BMI) ≥18.5 and BMI ≤30.0 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation Exclusion criteria: Clinically relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Clinically relevant surgery of gastrointestinal tract Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders Any relevant bleeding history History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator 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 might reasonably influence the results of the trial 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 four weeks prior to administration or during the trial Alcohol abuse (more than 60 g/day for men and more than 40 g/day for woman) 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 is of clinical relevance (especially hemoglobin and activated partial thromboplastin time) or positive drug or virus screening Planned surgeries within four weeks following the end-of study examination Inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study Intake of medication, which influences the blood clotting, i.e., acetylsalicylic acid, coumarin etc. within 10 days prior to administration Vulnerable subjects (e.g. persons kept in detention) Male subjects who do not agree to minimise the risk of female partners becoming pregnant from the first dosing day until the completion of the post study medical examination. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive since at least two months)

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate generation I<br> | Drug: Dabigatran etexilate generation I<br> <br> |
| Active Comparator: Dabigatran etexilate generation II<br> | Drug: Dabigatran etexilate generation II<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-infinity (area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| Cmax (maximum measured concentration of total dabigatran in plasma) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-infinity (area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| Cmax (maximum measured concentration of free dabigatran in plasma) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| AUC0-tz (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) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| AUCt1-t2 (area under the concentration time curve of the analyte in plasma over the time interval t1 to t2 with t1 = 0 and t2 = 24, 48, 72 hours) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| tmax (time from dosing to the maximum concentration of the analyte in plasma) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| λz (terminal rate constant in plasma) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| t1/2 (terminal half-life of the analyte in plasma) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| MRTpo (mean residence time of the analyte in the body after oral administration) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| CL/F (apparent clearance of the analyte in the plasma after extravascular administration) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose) |  | before drug administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours following drug administration |