Relative Bioavailability of Single Doses of Dabigatran Etexilate in Healthy Volunteers

Relative Bioavailability of Single Doses of 150 mg Dabigatran Etexilate (Capsule)When Administered Alone, After Seven Days of Dosing With 600 mg Rifampicin(Tablet), and Seven Days and Fourteen Days After Last Administration of Rifampicin in Healthy Male and Female Volunteers (an Open Label, Fixed Sequence, Phase I Study)

Study to investigate whether and to what extent the suggested P-glycoprotein (P-gp) inducer rifampicin affects plasma exposure of dabigatran.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dabigatran etexilate; Drug: Rifampicin

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male or female subjects according to the following criteria: based upon a complete medical history, including the physical examination, vital signs (BP, pulse rate), 12-lead ECG, clinical laboratory tests
• Age ≥18 and Age ≤45 years
• Body Mass Index (BMI) ≥18.5 and ≤29.9 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 gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorders

• Subjects who in the investigator's judgement were perceived as having an increased risk of bleeding, for example because of:

  • Hemorrhagic disorders or bleeding diathesis
  • Occult blood in faeces or haematocryal
  • Trauma or surgery within the last month or as long as an excessive risk of bleeding persisted after these events, or planned surgery during trial participation
  • History of arteriovenous malformation or aneurysm
  • History of gastroduodenal ulcer disease, gastrointestinal haemorrhage, and haemorrhoids
  • History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular bleeding
  • Use of drugs that may have interfered with haemostasis during trial conduct (e.g. acetylic salicylic acid or other non-steroidal anti-inflammatory drugs)
  • Relevant surgery of gastrointestinal tract
• 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 allergy/hypersensitivity (including drug allergy) which was deemed relevant to the trial as judged by the investigator
• Use of drugs which might have reasonably influenced 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 inhibitors or inducers of P-gp, CYP3A4, CYP2C9, or CYP2C19 trial (comment: CYP3A4 inhibitors are for example azole antimycotics, macrolides or grapefruit juice, CYP3A inducers are for example St. John's Wort or certain anticonvulsants)
• Intake of medication, which influences the blood clotting, i.e. acetylsalicylic acid, nonsteroidal anti-rheumatic drugs, cumarin, etc. within 14 days prior to screening or during the trial
• Participation in another trial with an investigational drug within one month prior to administration or during the trial
• Alcohol abuse (more than 60 g/day in males, more than 40 g/day in females)
• Drug abuse
• Blood donation (more than 100 mL within 4 weeks prior to administration)
• Any laboratory value outside the reference range that was of clinical relevance
• Inability to comply with dietary regimen of study centre
• Previous intake of rifampicin

• For female subjects:

  • Pregnancy / positive pregnancy test, or planning to become pregnant during the study or within 1 month of study completion
  • No adequate contraception in women of childbearing potential
  • Lactation period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dabigatran etexilate; Four treatments of 150 mg Dabigatran etexilate (single oral administration) in a fixed sequence.; Single oral administration of dabigatran etexilate on Day 1;; Oral administration of 600 mg rifampicin q.d. in the evening for 7 days (Days 2 to 8) followed by an oral morning dose of dabigatran etexilate on Day 9;; Single oral administration of dabigatran etexilate on Day 16, after 7 days of rifampicin washout;; Single oral administration of dabigatran etexilate on Day 23, after 14 days of rifampicin washout

Drug: Dabigatran etexilate; 150 mg Dabigatran etexilate; Other Names: Pradaxa®; BIBR 1048 MS; Drug: Rifampicin; 600 mg Rifampicin; Other Names: Rifa® 600

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-inf) of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Maximum measured concentration (Cmax) of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 334hours after treatment on Day1, 9, 16 and 23

Secondary Outcome Measures

Outcome Measure	Time Frame
AUC0-inf of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Cmax of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Cmax of dabigatran etexilate	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Time from dosing to the maximum concentration (tmax) of dabigatran etexilate	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Cmax of BIBR 1087SE	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
tmax of BIBR 1087SE	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Cmax of BIBR 951BS	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
tmax of BIBR 951BS	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Area under the concentration-time curve over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
AUC0-tz of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Area under the concentration-time curve over the time interval from timepoints t1 to t2 (AUCt1-t2) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
AUCt1-t2 of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Area under the concentration-time curve over the time interval from 0 to 24 h (AUC0-24) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
AUC0-24 of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
tmax of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
tmax of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Terminal rate constant (λz) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
λz of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Terminal half-life (t1/2) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
t1/2 of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Mean residence time after oral administration (MRTpo) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
MRTpo of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Apparent clearance after extravascular administration (CL/F) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
CL/F of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) of free dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Vz/F of total dabigatran	30 min pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 and 34 hours after treatment on Day1, 9, 16 and 23
Amount that is eliminated in urine from the time interval 0- 24h (Ae0-24) of total dabigatran	Day 1 and 9
Fraction excreted unchanged in urine from time point 0-24h (fe0-24) of total dabigatran	Day 1 and 9
Renal clearance from the time point 0 until the point 0-24h (CLR, 0-24) of total dabigatran	Day 1 and 9
Ratio of 6-ß-hydroxycortisol/cortisol in morning spot urine as a marker of CYP 3A induction	Day 1 and 9

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Estimate): June 25, 2014
• Last Update Submitted That Met QC Criteria: June 24, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Dabigatran; Rifampin
• Other Study ID Numbers: 1160.100