Relative Bioavailability of Dabigatran and Atorvastatin in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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To investigate the bioavailability of dabigatran with and without concomitant administration of atorvastatin and the bioavailability of atorvastatin with and without concomitant administration of dabigatran etexilate

Official Title
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Relative Bioavailability of Dabigatran and Atorvastatin After 150 mg BID Dabigatran Etexilate and Atorvastatin at 80 mg QD Alone or Following Concomitant Multiple Oral Administrations in Healthy Male and Female Volunteers (an Open-label, Randomised, Multiple-dose, Three-way Crossover Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dabigatran
* Drug: Atorvastatin


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 ≤65 years BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index) Liver transaminases (ALT; aspartate aminotransferase (AST); GGT) and creatin kinase (CK) are to be within the normal range Haemoglobin values within the normal range Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation. Exclusion Criteria: Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Relevant surgery of gastrointestinal tract History of any bleeding disorder or acute blood coagulation defect History or presence of acute liver disease History or presence of myopathy 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 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 two months prior to administration or during the trial Alcohol abuse (more than 60 g/day) Drug abuse Within 5 days of study medication no intake of grapefruit, grapefruit juice, or products containing grapefruit juice, Seville oranges, garlic supplements, or St. John's Wort Blood donation (more than 100 mL within four weeks prior to administration o 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 Inability to comply with dietary regimen of study centre Females of child bearing potential who are pregnant, breast feeding or who are either not surgically sterile or are sexually active and not using an acceptable form of contraception as either the oral contraceptives since at least two months or the double barrier method, i.e. intrauterine device with spermicide and condom for the male partner Male subjects will not agree to minimise the risk of female partners becoming pregnant from the first dosing day until 3 months after the completion of the post study medical. 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 month) Planned surgeries within four weeks following the end-of study examination Intake of medication, which influences the blood clotting, i.e., acetylsalicylic acid, cumarin etc. The subject is not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions Vulnerable subjects (e.g. persons kept in detention).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 plus atorvastatin<br> | Drug: Dabigatran<br> <br> Drug: Atorvastatin<br> <br> |
| Active Comparator: dabigatran<br> | Drug: Dabigatran<br> <br> |
| Active Comparator: atorvastatin<br> | Drug: Atorvastatin<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 at steady state over one dosing interval ( AUCτ,ss) |  | Day 4 | 
| Maximum concentration of the analyte in plasma at steady state (Cmax,ss) |  | 2 hours before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours after drug administration on day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of the analyte in plasma from the time point 0 after the last dose at steady state to the last quantifiable analyte plasma concentration within the uniform dosing interval τ (AUC0-tz,ss) |  | Up to day 7 after administration | 
| Time of last measurable concentration of the analyte in plasma within the dosing interval τ at steady state (tz,ss) |  | Up to day 7 after administration | 
| Time from last dosing to the maximum concentration of the analyte in plasma at steady state (tmax,ss) |  | Up to day 7 after administration | 
| Apparent clearance of the analyte in the plasma at steady state after extravascular multiple dose administration (CL/Fss) |  | Up to day 7 after administration | 
| Minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ (Cmin,ss) |  | 2 hours before and 0,5, 1, 1,5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours after drug administration | 
| Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval τ (tmin,ss ) |  | Up to day 7 after administration | 
| Pre-dose concentration of the analyte in plasma at steady state immediately before administration of the next dose (Cpre,ss) |  | 2 hours before drug administration on day 1, 2, 3 and 4 | 
| Mean residence time of the analyte in the body at steady state after p.o. administration (MRTp.o.,ss) |  | Up to day 7 after administration | 
| Apparent volume of distribution during the terminal phase λz at steady state following an extravascular administration (Vz/Fss) |  | Up to day 7 after administration | 
| Amount of analyte that was eliminated in urine at steady state over an uniform dosing interval τ (Aeτ,ss) |  | Day 4 and 5 after administration | 
| Fraction of parent drug eliminated in urine at steady state over a uniform dosing interval τ (feτ,ss) |  | Day 4 and 5 after administration | 
| Renal clearance of the analyte at steady state determined over the dosing interval τ (CLR,ss) |  | Day 4 and 5 after administration | 
| Maximum effect ratio at steady state (ERmax_ss) for activated thrombin time (aPTT) and ecarin clotting time (ECT) |  | Up to day 7 after administration | 
| Area under the effect curve (baseline corrected) (AUECτ,ss) for aPTT and ECT |  | Day 4 and 5 | 
| Change from baseline in blood pressure and puls rate (BP, PR) |  | Baseline, day 78 | 
| Change from baseline in physical examination |  | Baseline, day 78 | 
| Change from baseline in 12-lead electrocardiogram |  | Baseline, day 78 | 
| Change from baseline in clinical laboratory tests |  | Baseline, day 78 | 
| Number of Participants with Serious and Non-Serious Adverse Events |  | Up to day 78 | 
| Assessment of tolerability by investigator on a four point scale (good, satisfactory, not satisfactory, bad) |  | Day 78 | 
| Ecarin clotting time (ECT) prolongation at trough (ER(pre,ss)) |  | Up to day 7 after administration | 
| Amount of total active HMG-CoA reductase inhibitors in plasma |  | Up to day 7 after administration | 
| Activated partial thromboplastin time (aPTT) prolongation at trough (ER(pre,ss)) |  | Up to day 7 after administration |