Relative Bioavailability of Single Oral Doses of Dabigatran Etexilate With or Without Oral Administration of Verapamil in Two Different Dosages in Healthy Male and Female Volunteers

Relative Bioavailability of Single Oral Doses of 150 mg Dabigatran Etexilate With or Without Oral Administration of Verapamil in Two Different Dosages (240 mg and 480 mg Daily) (Open-label, Fixed-sequence Design), and Relative Bioavailability of Single Oral Doses of 150 mg Dabigatran Etexilate Given With or Without Single Oral Doses of 120 mg (IR) or 240 mg (ER) of Verapamil Administered at Different Time Points Relative to Dabigatran Etexilate Dosing in Healthy Male and Female Volunteers (Open-label, Randomised, Five-way Crossover Design, Phase I Study)

To investigate whether and to what extent the P-glycoprotein inhibitor (P-gp) verapamil affects the pharmacokinetic parameters of dabigatran with verapamil given at different dosages, in different formulations (immediate release (IR) and extended release (ER)), and in different intervals in relation to the dabigatran dose.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Verapamil; Drug: dabigatran; Drug: Verapamil ER

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
2. Age ≥18 and ≤55 years
3. Body mass index (BMI) ≥18.5 and BMI ≤29.9 kg/m2
4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation

Exclusion criteria:

1. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
2. Relevant surgery of gastrointestinal tract
3. History of any bleeding disorder or acute blood coagulation defect
4. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
5. History of relevant orthostatic hypotension, fainting spells or blackouts
6. Chronic or relevant acute infections
7. History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator
8. Pulse rate below 50 bpm and or systolic blood pressure <90 mm Hg at screening. ECG: PR >170 ms (Part 1), AV block ≥1st degree (Part 2) at screening
9. Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within four weeks prior to administration or during the trial, especially intake of medication, which influences the blood clotting, i.e., acetylsalicylic acid, cumarin etc.
10. Participation in another trial with an investigational drug within two months prior to administration or during the trial
11. Smoker (more than 15 cigarettes or 3 cigars or 3 pipes per day)
12. Alcohol abuse (more than 60 g/day for men and more than 40 g/day for women)
13. Drug abuse
14. Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
15. Excessive physical activities (within one week prior to administration or during the trial)
16. Any laboratory value outside the reference range that is of clinical relevance
17. Planned surgeries within four weeks following the end-of study examination

18. The subject is not able to understand and comply with protocol requirements, instructions, protocol-stated restrictions and dietary regimen of study centre

    For male subjects:

19. Male subjects who do not agree to minimise the risk of female partners becoming pregnant from the first dosing day until 3 months after the completion of the post study medical. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive since at least two month)

    For female subjects:

20. Pregnancy / positive pregnancy test, or planning to become pregnant during the study or within 1 month of study completion
21. No adequate contraception during the study and until 1 month of study completion, i.e. implants, injectables, combined oral contraceptives, IUD (intrauterine device), sexual abstinence (for at least 1 month prior to enrolment), vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (incl. hysterectomy). Females, who have not a vasectomised partner, are not sexually abstinent or surgically sterile will be asked to additionally use barrier contraception methods (e.g. condom, diaphragm with spermicide)
22. Lactation period

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: Fixed sequence; Treatments will be given in a fixed sequence	Drug: Verapamil; Drug: dabigatran
Experimental: Crossover; Treatments will be given in randomized sequences	Drug: Verapamil; Drug: dabigatran; Drug: Verapamil ER

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AUC0-infinity (area under the concentration-time curve of total dabigatran over the time interval from 0 extrapolated to infinity)	up to 107 hours
Cmax (maximum measured concentration of total dabigatran)	up to 107 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-infinity (area under the concentration-time curve of free dabigatran over the time interval from 0 extrapolated to infinity)		up to 107 hours
Cmax (maximum measured concentration of free dabigatran)		up to 107 hours
AUC0-infinity (area under the concentration-time curve of verapamil over the time interval from 0 extrapolated to infinity)		up to 107 hours
Cmax (maximum measured concentration of verapamil)		up to 107 hours
AUC0-tz (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)		up to 107 hours
AUC0-24 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 h after the administration)		up to 107 hours
tmax (time from dosing to the maximum concentration of the analyte in plasma)		up to 107 hours
λz (terminal rate constant in plasma)		up to 107 hours
t1/2 (terminal half-life of the analyte in plasma)		up to 107 hours
MRTpo (mean residence time of the analyte in the body after oral administration)		up to 107 hours
CL/F (apparent clearance of the analyte in the plasma after extravascular administration)		up to 107 hours
Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose)		up to 107 hours
AUCτ,ss (area under the concentration-time curve of verapamil within the uniform dosing interval τ)		up to 107 hours
AUC0-tz,ss (area under the concentration-time curve of verapamil from the time point 0 after the last dose at steady state to the last quantifiable analyte plasma concentration within the uniform dosing interval τ)		up to 107 hours
Cmax,ss (maximum concentration of verapamil at steady state)		up to 107 hours
tz,ss (time of last measureable concentration of verapamil within the dosing interval τ at steady state)		up to 107 hours
tmax,ss (time from last dosing to the maximum concentration of verapamil at steady state on day 4)		up to 107 hours
CL/F,ss (apparent clearance of verapamil at steady state after extravascular multiple dose administration)		up to 107 hours
Cmin,ss (minimum measured concentration of verapamil at steady state over a uniform dosing interval τ)		up to 107 hours
tmin,ss (time from last dosing to the minimum concentration of verapamil at steady state over a uniform dosing interval τ)		up to 107 hours
Cpre,ss (predose concentration of verapamil at steady state immediately before administration of the next dose)		up to 107 hours
Cavg (Average concentration of verapamil at steady state)		up to 107 hours
MRTpo,ss (mean residence time of verapamil in the body at steady state after oral administration)		up to 107 hours
Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following an extravascular administration)		up to 107 hours
Ae0-24 (amount of dabigatran that is eliminated in urine from the time interval 0-24h)		up to 107 hours
fe0-24 (fraction of administered drug excreted unchanged in urine from time point 0- 24h)		up to 107 hours
CLR0-24 (renal clearance of dabigatran from the time point 0 until the time point 24h )		up to 107 hours
AUEC0-24 (area under the effect curve)	for ecarin clotting time and thrombin time	up to 107 hours
ERmax (maximum effect ratio)	for ecarin clotting time and thrombin time	up to 107 hours
Occurence of Adverse Events		within 5 days after last drug administration
Assessment of Tolerability by investigator		within 5 days after last drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): August 1, 2008

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; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Calcium Channel Blockers; Dabigatran; Verapamil
• Other Study ID Numbers: 1160.74