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

Phase 1
Completed
Conditions
Healthy
Interventions
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
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.
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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
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Study & Design

Study Type
INTERVENTIONAL
Study Design
CROSSOVER
Arm && Interventions
GroupInterventionDescription
quinidinedabigatran etexilatequinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
dabigatran etexilatedabigatran etexilatequinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
dabigatran etexilatequinidinequinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
quinidinequinidinequinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order
Primary Outcome Measures
NameTimeMethod
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
NameTimeMethod
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 Eventsup to day 26
Abnormal findings in physical examinationup 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 prolongationup to day 26
Changes in clinical laboratory testsup to day 26
Number of patients with adverse events leading to treatment discontinuationup 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
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