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

Information source: Boehringer Ingelheim
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Healthy

Intervention: dabigatran etexilate (Drug); quinidine (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Boehringer Ingelheim

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.

Clinical Details

Official title: 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 design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Differences between treatments in systolic blood pressure profiles (using area under the BP-time curve)

Incidence of symptomatic hypotension

Secondary outcome:

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)

Eligibility

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Additional Information

Starting date: March 2009
Last updated: June 20, 2014

Page last updated: August 23, 2015

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