Relative Bioavailability of Single Doses of Dabigatran Etexilate in Healthy Volunteers

Condition(s) targeted: Healthy

Intervention: Dabigatran etexilate (Drug); Rifampicin (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Boehringer Ingelheim

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

Official title: 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 design: Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-inf) of total dabigatran

Maximum measured concentration (Cmax) of total dabigatran

Secondary outcome:

AUC0-inf of free dabigatran

Cmax of free dabigatran

Cmax of dabigatran etexilate

Time from dosing to the maximum concentration (tmax) of dabigatran etexilate

Cmax of BIBR 1087SE

tmax of BIBR 1087SE

Cmax of BIBR 951BS

tmax of BIBR 951BS

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

AUC0-tz of total dabigatran

Area under the concentration-time curve over the time interval from timepoints t1 to t2 (AUCt1-t2) of free dabigatran

AUCt1-t2 of total dabigatran

Area under the concentration-time curve over the time interval from 0 to 24 h (AUC0-24) of free dabigatran

AUC0-24 of total dabigatran

tmax of free dabigatran

tmax of total dabigatran

Terminal rate constant (λz) of free dabigatran

λz of total dabigatran

Terminal half-life (t1/2) of free dabigatran

t1/2 of total dabigatran

Mean residence time after oral administration (MRTpo) of free dabigatran

MRTpo of total dabigatran

Apparent clearance after extravascular administration (CL/F) of free dabigatran

CL/F of total dabigatran

Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) of free dabigatran

Vz/F of total dabigatran

Amount that is eliminated in urine from the time interval 0- 24h (Ae0-24) of total dabigatran

Fraction excreted unchanged in urine from time point 0-24h (fe0-24) of total dabigatran

Renal clearance from the time point 0 until the point 0-24h (CLR, 0-24) of total dabigatran

Ratio of 6-ß-hydroxycortisol/cortisol in morning spot urine as a marker of CYP 3A induction

Minimum age: 18 Years. Maximum age: 45 Years. Gender(s): Both.

Criteria:

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

Starting date: June 2009
Last updated: June 24, 2014