Relative Bioavailability of Single Doses of Dabigatran Etexilate When Administered Alone or in Combination With a Single Dose of Ketoconazole or in Combination With q.d. Ketoconazole at Steady State in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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To investigate whether and to what extent the P-glycoprotein (P-gp) inhibitor ketoconazole affects plasma exposure of dabigatran.

Official Title
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Relative Bioavailability of Single Doses of 150 mg Dabigatran Etexilate (Capsule) When Administered Alone or in Combination With a Single Dose of 400 mg Ketoconazole (Tablet) or in Combination With 400 mg q.d. Ketoconazole (Tablet) at Steady State in Healthy Male and Female Volunteers (an Open Label, Fixed Sequence, Phase I Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Ketoconazole


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 ≥21 and ≤50 years BMI range ≥18.5 and ≤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, and intake of drugs which might reasonably influence the results of the trial within four weeks prior to administration or during the trial (e.g. P-gp inducers) 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) 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 Exclusion criteria that were specific for this study: Intake of medication, which influences the blood clotting, such as acetylsalicylic acid and oral vitamin K antagonists For female subjects: Pregnancy / positive pregnancy test, or planning to become pregnant during the study or within 1 month of study completion No adequate contraception during the study and until 1 month of study completion, i.e. implants, injectables, combined oral contraceptives, IUD [intrauterine device], sexual abstinence (for at least 1 month prior to enrolment), or surgical sterilisation (incl. hysterectomy). Females, who were not surgically sterile were asked to additionally use barrier contraception methods (e.g. condom, diaphragm with spermicide) Lactation period

Ages Eligible for Study
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Minimum Age: 21 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate + Ketoconazole<br>Period 1 - Dabigatran etexilate Period 2 - Dabigatran etexilate and single dose of 400 mg Ketoconazole on Day 8 and 9 Period 3 - Dabigatran etexilate and multiple doses of 400 mg Ketoconazole on Day 10 to 16 | Drug: Dabigatran etexilate<br> <br> Drug: Ketoconazole<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 for total dabigatran |  | up to Day 16 | 
| Maximum measured concentration of the analyte in plasma for total dabigatran |  | up to Day 16 | 

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 extrapolated to infinity for free dabigatran |  | up to Day 16 | 
| Maximum measured concentration of the analyte in plasma for free dabigatran |  | up to Day 16 | 
| Maximum measured concentration of the analyte in plasma for dabigatran and BIBR 1087 SE, BIBR 951 BS |  | up to Day 16 | 
| Time from dosing to the maximum concentration of the analyte in plasma for dabigatran and BIBR 1087 SE, BIBR 951 BS |  | up to Day 16 | 
| 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 for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Area under the concentration-time curve of the analyte in plasma over the time interval from timepoints t1 to t2 for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 h for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Time from dosing to the maximum concentration of the analyte in plasma for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Terminal rate constant of the analyte in plasma for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Terminal half-life of the analyte in plasma for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Mean residence time of the analyte in the body after oral administration for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Apparent clearance of the analyte in the plasma after extravascular administration for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Apparent volume of distribution during the terminal phase λz following an extravascular dose for dabigatran | Dabigatran after each single dose (free and total after conjugate cleavage) | up to Day 16 | 
| Changes from baseline in Vital signs (blood pressure [BP], pulse rate) |  | up to 14 days after last drug administration | 
| Changes from baseline in 12-lead ECG |  | up to 14 days after last drug administration | 
| Changes from baseline in Clinical laboratory tests (haematology, clinical chemistry, and urinalysis) |  | up to 14 days after last drug administration | 
| Number of patients with adverse events |  | up to 14 days after last drug administration | 
| Assessment of tolerability by the investigator |  | up to 14 days after last drug administration |