Bioavailability of Different Applications of Dabigatran in Healthy Volunteers

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Dabigatran etexilate powder; Drug: Dabigatran etexilate capsule; Drug: Dabigatran etexilate pellets

• Registration Number: NCT02171611
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

To determine the relative bioavailability of 150 mg of dabigatran etexilate as pellets on food and of 150 mg of dabigatran etexilate as powder resolved in reconstitution solution, both with 150 mg of dabigatran etexilate as capsule in healthy volunteers

Detailed Description

Not available

Study Timeline

• Study Start: 2009-03
• Primary Completion: 2009-05
• Study First Submitted: 2014-06-20
• Study First Submitted QC: 2014-06-20
• Study First Posted: 2014-06-24
• Results First Submitted: 2017-03-15
• Results First Submitted QC: 2017-03-15
• Status Verified: 2017-04
• Results First Posted: 2017-04-25
• Last Update Submitted: 2017-04-27
• Last Update Posted: 2017-05-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests
• Age ≥18 and age ≤50 years
• BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index)
• 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 BP, PR and 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 could reasonably influence the results of the trial (especially unspecific inducing agents like St. John´s wort (Hypericum perforatum) 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 two months prior to administration or during the trial

• Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day)

• Inability to refrain from smoking on trial days

• 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 was 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 Torsade de Pointes (e.g. heart failure, hypokalemia, family history of Long QT Syndrome)

• For female subjects:

  • Positive pregnancy test, pregnancy or planning to become pregnant during the study or within 1 month after study completion
  • No adequate contraception during the study and until 1 month after study completion, i.e. not any of the following: implants, injectables, combined oral contraceptives, intrauterine device (IUD), sexual abstinence for at least 1 month prior to enrolment, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who did not have a vasectomised partner, were not sexually abstinent or surgically sterile were to be asked to use an additional barrier method (e.g. condom, diaphragm with spermicide)
  • Lactation

• Intake of medication, which influences the blood clotting, i.e. acetylsalicylic acid, oral vitamin K antagonists etc.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Dabigatran etexilate powder	Dabigatran etexilate powder	-
Dabigatran etexilate capsule	Dabigatran etexilate capsule	-
Dabigatran etexilate pellets	Dabigatran etexilate pellets	-

Primary Outcome Measures

Name	Time	Method
Cmax for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Maximum measured concentration of the analyte in plasma (Cmax) for free dabigatran
AUC0-inf for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) for total dabigatran.
AUC0-inf for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) for free dabigatran.
Cmax for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Maximum measured concentration of the analyte in plasma (Cmax) for total dabigatran.

Secondary Outcome Measures

Name	Time	Method
λz for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Terminal rate constant in plasma (λz) for total dabigatran.
AUC0-tz for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) for free dabigatran.
t1/2 for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Terminal half-life of the analyte in plasma (t1/2) for free dabigatran.
AUC0-tz for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) for total dabigatran.
Tmax for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Time from dosing to the maximum concentration of the analyte in plasma (tmax) for free dabigatran
t1/2 for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Terminal half-life of the analyte in plasma (t1/2) for total dabigatran
CL/F for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Apparent clearance of the analyte in plasma following extravascular administration (CL/F) for total dabigatran.
Vz/F for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) for total dabigatran.
Tmax for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Time from dosing to the maximum concentration of the analyte in plasma (tmax) for total dabigatran
λz for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
MRTpo for Total Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Mean residence time of the analyte in the body after po administration (MRTpo) for total dabigatran.
MRTpo for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Mean residence time of the analyte in the body after po administration (MRTpo) for free dabigatran.
Percentage of Participants With Findings in Physical Examination, Vital Signs , Pulse Rate (PR)), 12-lead ECG, Clinical Laboratory Tests.	From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days.	Percentage of participants with findings in Physical examination, Vital signs (blood pressure (BP), pulse rate (PR)), 12-lead ECG (electrocardiogram), Clinical laboratory tests (haematology, clinical chemistry and urinalysis). Relevant findings or worsening of baseline conditions were reported as Adverse events.; There were no clinically relevant finding reported for Physical examination, Vital signs (blood pressure, pulse rate), 12-lead ECG and Clinical laboratory tests.
Percentage of Participants With Drug-related Adverse Events	From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days.	Percentage of participants with investigator defined drug-releated Adverse events.
CL/F for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Apparent clearance of the analyte in plasma following extravascular administration (CL/F) for free dabigatran.
Vz/F for Free Dabigatran	-0:30 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.	Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) for free dabigatran.
Assessment of Tolerability by Investigator.	From first drug administration until 7 days after the last drug administration of Dabigatran, ie., up to 10 days.	Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory and bad.