Single and Multiple Oral Doses of Dabigatran Etexilate in Healthy Chinese Subjects

Study Overview
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Brief Summary
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The objective of the current study is to investigate safety, tolerability and, pharmacokinetics of dabigatran etexilate following oral administration of single and multiple oral doses (110mg, 150 mg b.i.d., 7 days) in healthy Chinese subjects.

Official Title
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Safety, Tolerability and Pharmacokinetics Study After Single and Multiple Oral Doses of Dabigatran Etexilate Capsule (110mg,150 mg b.i.d., 7 Days) in Healthy Chinese Subjects (Open Label Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran etexilate low
* Drug: Dabigatran etexilate high


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR and body temperature), 12-lead ECG, clinical laboratory tests No finding of clinical relevance. No evidence of a clinically relevant concomitant disease. Age: ≥18 and ≤45 years. Body Mass Index (BMI): ≥18 and <25 kg/m2. Signed and dated written informed consent prior to admission to the trial in accordance with Chinese GCP. Exclusion Criteria: Current gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders. Subject can not use an adequate form of contraception from the time of the first dose on Day 1 up to end-of study examination. Current diseases of the central nervous system (such as epilepsy), or psychiatric disorders or neurological disorders. History of clinically significant orthostatic hypotension, clinically significant current or past fainting spells or blackouts. Chronic or relevant acute infections. History of allergy/hypersensitivity (including drug allergy) which was deemed relevant to the safety assessment as judged by the investigator (excluding asymptomatic seasonal rhinitis/hay fever) any bleeding disorder including prolonged or habitual bleeding other hematologic diseases. cerebral bleeding (e.g. after a car accident). concussions (head trauma resulting in injuring to brain) with or without loss of consciousness. Intake of drugs with a long half-life (> 24 hours) within at least 1 month or less than 10 half-lives, whichever was shorter, of the respective drug prior to administration or during the trial. Use of aspirin (including over-the-counter medications), antiplatelet agents like ticlopidine or dipyridamole, chronic administration of non-steroidal anti-inflammatory drugs (NSAID), coumadin like anticoagulants, chronic use of corticosteroids, heparin or fibrinolytic agents within 14 days prior to administration up to end-of-study examination. Participation in another trial with an investigational drug within 3 months prior to administration up to end-of-study examination. Smoker (>10 cigarettes/day or inability to refrain from smoking during the trial). Alcohol abuse (more than 60 g/day; confirmed by interview). Drug abuse (confirmed by interview). Blood donation (more than 100 mL from 3 months prior to screening and any blood donation from screening up to end-of-study examination). Excessive physical activities (within 7 days prior to the first drug administration up to end-of-study examination). Any laboratory value outside the reference range that is of clinical relevance. Known hypersensitivity to the investigational drug or its excipients. Subject who was judged ineligible by the investigator or the sub-investigator. History of any familial bleeding disorder. Thrombocytes < 100×109 . Pregnant female subjects.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate low<br> | Drug: Dabigatran etexilate low<br> <br> |
| Experimental: Dabigatran etexilate high<br> | Drug: Dabigatran etexilate high<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in physical examination |  | Day 1 and 14 | 
| Changes in vital signs |  | Day 1 to 14 | 
| Changes in 12-lead electrocardiogram (ECG) |  | Day 1, Day 4-10, day 14 | 
| Changes from baseline in laboratory examinations |  | Day 1, 2, 4, 7, 11, 14 | 
| Occurrence of adverse events |  | up to 7 days after last drug intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration of the analyte in plasma) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| tmax (time from dosing to maximum measured concentration of the analyte in plasma) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ after administration of the single dose on Day 1) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| AUC 0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable drug plasma concentration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| AUC0-∞ (amount of analyte that is eliminated in area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| %AUCtz-∞ (the percentage of the AUC0-∞ that is obtained by extrapolation) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| λz (terminal rate constant in plasma) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| t1/2, (terminal half-life of the analyte in plasma) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| MRTpo, (mean residence time of the analyte in the body after oral administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| CL/F, (apparent clearance of the analyte in plasma following extravascular administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after single dose of study drug | 
| Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| tmax,ss (time from last dosing to maximum concentration of the analyte in plasma at steady state) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| Cmin,ss (minimum concentration of the analyte in plasma at steady state over a uniform dosing interval τ) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| λz,ss (terminal rate constant in plasma at steady state) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| t1/2,ss (terminal half-life of the analyte in plasma at steady state) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| MRTpo,ss (mean residence time of the analyte in the body at steady state after oral administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular multiple dose administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following extravascular administration) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| RA,Cmax, (calculated as Cmax,ss/Cmax) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| RA,AUC, (calculated as AUCτ,ss/AUCτ,1) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug | 
| linearity index (LI) |  | Before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours after last multiple dose of study drug |