Safety and Pharmacokinetics of Quinidine Alone and in Combination With Dabigatran Etexilate

Study Overview
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Brief Summary
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Open-label, two-way crossover design with a quinidine sulfate run-in period followed by a randomised sequence of dabigatran etexilate plus quinidine sulfate or dabigatran etexilate alone to evaluate the safety of co-administration of dabigatran etexilate and quinidine. and the pharmacokinetic interaction between quinidine and dabigatran etexilate.

Official Title
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A Two-way Crossover Study to Evaluate the Safety and Pharmacokinetics of Quinidine Sulfate Alone (200 mg Orally q2h to a Maximum of 1,000 mg), Dabigatran Etexilate Alone (150 mg BID for Three Days), and the Co-administration of Dabigatran Etexilate (150 mg BID) With Quinidine Sulfate (200 mg q2h)

Conditions
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Healthy

Intervention / Treatment
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* Drug: dabigatran etexilate
* Drug: quinidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects Age ≥18 and Age ≤55 years Body Mass Index (BMI) ≥18.5 and BMI <30 kg/m2 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 Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (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 Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval 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 thirty days prior to administration or during the trial Inability to refrain from smoking on trial days 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 is of clinical relevance Inability to comply with dietary regimen of trial site A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) Taking drugs which are known P-gp and/or CYP3A4 inhibitors or inducers (verapamil, phenothiazine antipsychotics, macrolide antibiotics (clarithromycin, erythromycin), antifungal drugs, antiviral drugs (protease inhibitors like nelfinavir) or St. John´s Wort) within the last 4 weeks before screening Taking drugs which are known CYP2D6 substrates (antidepressants, antiarrhythmics, beta blockers) within the last 2 weeks before screening For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test No adequate contraception e.g., sterilisation, IUD (intrauterine device), have not been using a barrier method of contraception for at least 3 months prior to participation in the study Are not willing or are unable to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during and up to 2 months after completion/termination of the trial Chronic use of oral contraception or hormone replacement containing ethinyl estradiol as the only method of contraception Partner is unwilling to use condoms Currently lactating

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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 etexilate<br>quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order | Drug: dabigatran etexilate<br> <br> Drug: quinidine<br> <br> |
| Experimental: quinidine<br>quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order | Drug: dabigatran etexilate<br> <br> Drug: quinidine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences between treatments in systolic blood pressure profiles (using area under the BP-time curve) |  | -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose | 
| Incidence of symptomatic hypotension |  | -0:15 before, and every 15 minutes for 2 hours post-dose, 3, 4 and 12 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the effect curve (AUEC) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT) |  | up to 48 hours after last dose | 
| Maximum effect ratio (ERmax) for activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT) |  | up to 48 hours after last dose | 
| Occurrence of Adverse Events |  | up to day 26 | 
| Abnormal findings in physical examination |  | up to day 26 | 
| Changes from baseline in Vital Signs (Blood Pressure (BP), Heart Rate (HR)) |  | up to day 26 | 
| Changes from baseline in 12-lead ECG (electrocardiogram) |  | up to day 26 | 
| Changes from baseline in QT prolongation |  | up to day 26 | 
| Changes in clinical laboratory tests |  | up to day 26 | 
| Number of patients with adverse events leading to treatment discontinuation |  | up to day 26 | 
| AUC (area under the concentration-time curve of the analyte in plasma) |  | up to 48 hours after the last dose | 
| Cmax (maximum measured concentration of the analyte in plasma) |  | up to 48 hours after the last dose | 
| tmax (time from dosing to the maximum concentration of the analyte in plasma) |  | up to 48 hours after the last dose | 
| λz (terminal rate constant in plasma) |  | up to 48 hours after the last dose | 
| t½ (terminal half-life of the analyte in plasma) |  | up to 48 hours after the last dose | 
| Cpre (pre-dose concentration of the analyte in plasma immediately before administration of the following dose) |  | up to 48 hours after the last dose | 
| MRTpo,ss (mean residence time of the analyte in the body at steady state after po administration) |  | up to 48 hours after last dose | 
| Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following an extravascular dose) |  | up to 48 hours after last dose | 
| CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular administration) |  | up to 48 hours after last dose | 
| Cavg (average concentration of the analyte in plasma under steady-state conditions) |  | up to 48 hours after last dose | 
| Cmin,ss (minimum measured concentration of the analyte in plasma at steady state) |  | up to 48 hours after last dose | 
| PTF (peak trough fluctuation) |  | up to 48 hours after last administration | 
| RAUCt1-t2, MET, 5 (ratio of AUCt1-t2 of 3-OH-quinidine/quinidine) |  | up to 48 hours after last dose |