Tolerability of BIBR 953 ZW IV and Bioavailability of BIBR 1048 Tablet and Solution in Healthy Males

Study Overview
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Brief Summary
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Two substudies to assess (1) the tolerability of BIBR 953 ZW intravenous infusion at 0.1, 1 and 5 mg BIBR 953 ZW and (2) the absolute bioavailability of 100mg BIBR 1048 administered as 'acid free' tablet formulation (TF1) and (3) the bioavailability of the 100 mg tablet of BIBR 1048 relative to the tartaric acid solution of 100 mg dose strength and (4) the absolute bioavailability of the 100 mg tartaric acid solution of BIBR 1048 MS.

Official Title
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Tolerability of Single Rising Doses of 0.1 mg, 1 mg, and 5 mg BIBR 953 ZW IV (Placebo-controlled in Each Dose Group; Substudy 1) and Absolute and Relative Bioavailability of 100mg BIBR 1048 Tablet and of Solution and of 1 mg or 5 mg BIBR 953 ZW IV (Randomized, Three-way Crossover; Substudy 2).

Conditions
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Healthy

Intervention / Treatment
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* Drug: BIBR 953 ZW IV
* Drug: BIBR 1048 MS tablet
* Drug: BIBR 1048 MS oral solution
* Drug: BIBR 953 ZW IV Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects as determined by results of screening Signed written informed consent in accordance with GCP and local legislation Age ≥ 18 and ≤ 50 years Broca ≥ - 20% and ≤ + 20% Exclusion Criteria: Any findings of the medical examination (including blood pressure, pulse rate and ECG) deviating from normal and of clinical relevance History or current gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic, hormonal disorders History of orthostatic hypotension, fainting spells and blackouts Diseases of the central nervous system (such as epilepsy) or psychiatric disorders Chronic or relevant acute infections History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator any bleeding disorder including prolonged or habitual bleeding other hematologic disease cerebral bleeding (e.g. after a car accident) commotio cerebri Intake of drugs with a long half-life (>24 hours) within 1 month prior to administration Use of any drugs which might influence the results of the trial within 10 days prior to administration or during trial Participation in another trial with an investigational drug within 2 months prior to administration or during trial Smoker (> 10 cigarettes or 3 cigars or 3 pipes/day) or inability to refrain from smoking on study days Alcohol abuse (> 60 g/day) Drug abuse Blood donation within 1 month prior to administration or during the trial Excessive physical activities within 5 days prior to administration or during the trial Any laboratory value outside the clinically accepted reference range History of any familial bleeding disorder Thrombocytes < 150000/µl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBR 953 ZW IV<br> | Drug: BIBR 953 ZW IV<br> <br> |
| Active Comparator: BIBR 1048 MS oral solution<br> | Drug: BIBR 1048 MS oral solution<br> <br> |
| Experimental: BIBR 1048 MS tablet<br> | Drug: BIBR 1048 MS tablet<br> <br> |
| Placebo Comparator: BIBR 953 ZW IV Placebo<br> | Drug: BIBR 953 ZW IV Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-inf (Area under the plasma concentration-time curve extrapolated to infinity) |  | up to 48 hours after drug administration | 
| AUC0-tf (Area under the plasma concentration-time curve up to the last quantifiable plasma concentration) |  | up to 48 hours after drug administration | 
| Cmax (Maximum plasma concentration after oral administration) |  | up to 48 hours after drug administration | 
| Cumulative urinary excretion of BIBR 953 ZW administered intravenously |  | up to 48 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in activated partial thromboplastin time (aPTT ) |  | up to 48 hours after drug administration | 
| changes in prothrombin time (PT) |  | up to 48 hours after drug administration | 
| C29 (Plasma concentration of BIBR 953 ZW at 29 minutes after the start of the 30 min. infusion) |  | 29 minutes after start of infusion | 
| t1/2 (terminal half-life) |  | up to 48 hours after infusion | 
| CLtot (total clearance of drug from plasma) |  | up to 48 hours after infusion | 
| CLren (renal clearance from plasma) |  | up to 48 hours after infusion | 
| MRTdisp (Mean time of residence of drug molecules in the body after intravascular administration) |  | up to 48 hours after infusion | 
| Vss (apparent volume of distribution at steady state) |  | up to 48 hours after infusion | 
| Vz (Apparent volume of distribution during the terminal elimination phase) |  | up to 48 hours after infusion | 
| MRTtot (total mean residence time) |  | up to 48 hours after oral administration | 
| CLtot/F (total clearance after oral administration) |  | up to 48 hours after oral administration | 
| tmax (time to reach the peak plasma concentration) |  | up to 48 hours after oral administration | 
| Vz/F (apparent volume of distribution of the terminal elimination phase after oral administration) |  | up to 48 hours after oral administration | 
| changes in Ecarin clotting time (ECT) |  | up to 48 hours after drug administration | 
| changes in thrombin time (TT) |  | up to 48 hours after drug administration | 
| changes in vital signs (systolic and diastolic blood pressure, pulse rate) |  | up to 1 month | 
| changes in electrocardiogram |  | up to 1 month | 
| occurrence of adverse events |  | up to 1 month |