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

Overview

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.

Full Title of Study: “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)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2009

Interventions

  • Drug: dabigatran etexilate
  • Drug: quinidine

Arms, Groups and Cohorts

  • Experimental: dabigatran etexilate
    • quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
  • Experimental: quinidine
    • quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Boehringer Ingelheim
  • Provider of Information About this Clinical Study
    • Sponsor

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