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

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)

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: quinidine; Drug: dabigatran etexilate

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dabigatran etexilate; quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order	Drug: quinidine; Drug: dabigatran etexilate
Experimental: quinidine; quinidine run-in, followed by dabigatran+quinine and dabigatran alone in randomized order	Drug: quinidine; Drug: dabigatran etexilate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: June 20, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Estimate): June 24, 2014
• Last Update Submitted That Met QC Criteria: June 20, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Protease Inhibitors; Membrane Transport Modulators; Cytochrome P-450 Enzyme Inhibitors; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Adrenergic alpha-Antagonists; Dabigatran; Quinidine
• Other Study ID Numbers: 1160.90