Clinical trial NCT02173717: Relative Bioavailability of Single Doses of Dabigatran Etexilate in Healthy Volunteers
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-06-25
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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


Eligibility 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

Primary outcomes:
measure: Area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC0-inf) of total dabigatran
timeFrame: 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
measure: Maximum measured concentration (Cmax) of total dabigatran
timeFrame: 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 outcomes:
measure: AUC0-inf of free dabigatran
timeFrame: 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
measure: Cmax of free dabigatran
timeFrame: 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
measure: Cmax of dabigatran etexilate
timeFrame: 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
measure: Time from dosing to the maximum concentration (tmax) of dabigatran etexilate
timeFrame: 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
measure: Cmax of BIBR 1087SE
timeFrame: 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
measure: tmax of BIBR 1087SE
timeFrame: 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
measure: Cmax of BIBR 951BS
timeFrame: 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
measure: tmax of BIBR 951BS
timeFrame: 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
measure: 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
timeFrame: 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
measure: AUC0-tz of total dabigatran
timeFrame: 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
measure: Area under the concentration-time curve over the time interval from timepoints t1 to t2 (AUCt1-t2) of free dabigatran
timeFrame: 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
measure: AUCt1-t2 of total dabigatran
timeFrame: 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
measure: Area under the concentration-time curve over the time interval from 0 to 24 h (AUC0-24) of free dabigatran
timeFrame: 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
measure: AUC0-24 of total dabigatran
timeFrame: 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
measure: tmax of free dabigatran
timeFrame: 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
measure: tmax of total dabigatran
timeFrame: 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
measure: Terminal rate constant (λz) of free dabigatran
timeFrame: 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
measure: λz of total dabigatran
timeFrame: 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
measure: Terminal half-life (t1/2) of free dabigatran
timeFrame: 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
measure: t1/2 of total dabigatran
timeFrame: 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
measure: Mean residence time after oral administration (MRTpo) of free dabigatran
timeFrame: 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
measure: MRTpo of total dabigatran
timeFrame: 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
measure: Apparent clearance after extravascular administration (CL/F) of free dabigatran
timeFrame: 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
measure: CL/F of total dabigatran
timeFrame: 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
measure: Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) of free dabigatran
timeFrame: 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
measure: Vz/F of total dabigatran
timeFrame: 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
measure: Amount that is eliminated in urine from the time interval 0- 24h (Ae0-24) of total dabigatran
timeFrame: Day 1 and 9
measure: Fraction excreted unchanged in urine from time point 0-24h (fe0-24) of total dabigatran
timeFrame: Day 1 and 9
measure: Renal clearance from the time point 0 until the point 0-24h (CLR, 0-24) of total dabigatran
timeFrame: Day 1 and 9
measure: Ratio of 6-ß-hydroxycortisol/cortisol in morning spot urine as a marker of CYP 3A induction
timeFrame: Day 1 and 9
Other outcomes:
Locations:
Study officials:
References: