Safety and Pharmacokinetics of Quinidine Alone and in Combination With Dabigatran Etexilate
- Registration Number
- NCT02171624
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 42
- 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.
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Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance
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Any evidence of a clinically relevant concomitant disease
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Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
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Surgery of the gastrointestinal tract (except appendectomy)
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Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
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History of relevant orthostatic hypotension, fainting spells or blackouts
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Chronic or relevant acute infections
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History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
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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
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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
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Participation in another trial with an investigational drug within thirty days prior to administration or during the trial
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Inability to refrain from smoking on trial days Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
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Alcohol abuse (more than 60 g/day)
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Drug abuse
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Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
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Excessive physical activities (within one week prior to administration or during the trial)
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Any laboratory value outside the reference range that is of clinical relevance
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Inability to comply with dietary regimen of trial site
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A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
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A history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
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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
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Taking drugs which are known CYP2D6 substrates (antidepressants, antiarrhythmics, beta blockers) within the last 2 weeks before screening
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description quinidine dabigatran etexilate quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order dabigatran etexilate dabigatran etexilate quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order dabigatran etexilate quinidine quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order quinidine quinidine quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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