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