Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of 150 mg Dabigatran Etexilate p.o. in Patients With Different Degrees of Renal Impairment in Comparison to Subjects With Normal Renal Function in a Monocentric, Open, Parallel-group Trial
Overview
- Phase
- Phase 1
- Intervention
- Dabigatran etexilate high dose
- Conditions
- Renal Insufficiency
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 35
- Primary Endpoint
- AUC0-infinity (area under the concentration time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
To assess the effect of different degrees of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran etexilate administered orally.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy male or female subjects determined by results of screening with a creatinine clearance \>80 mL/min (group 1, control group)
- •Renally impaired male or female subjects determined by results of screening with the following creatinine clearance results:
- •creatinine clearance \>50 - ≤80 mL/min (group 2)
- •creatinine clearance \>30 - ≤50 mL/min (group 3)
- •creatinine clearance ≤30 mL/min (group 4)
- •uraemia requiring maintenance dialysis (group 5)
- •Signed written informed consent in accordance with Good Clinical Practice (GCP) and local legislation
- •Age \>=18 and \<=75 years
- •BMI \>=18.0 and \<=32 kg/m2, at least 45 kg for females
Exclusion Criteria
- •Any finding of the medical examination (including blood pressure, pulse rate, and electrocardiogram) deviating from normal and of clinical relevance
- •Clinically relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic or hormonal disorders
- •Surgery of gastrointestinal tract (except appendectomy, cholecystectomy or herniotomy)
- •Clinically relevant diseases of the central nervous system
- •Relevant history of orthostatic hypotension, fainting spells or blackouts
- •Abnormal prothrombin time (PT), TT, aPTT (must be within the normal range after no more than one repeated test), thrombocytes \<150000/μl (two repeats of the first test)
- •Evidence of haematuria either macroscopically detectable or microscopic on urinalysis (normal microscopic results after no more than one repeated test)
- •Evidence of blood dyscrasia, haemorrhagic diathesis, severe thrombocytopenia, cerebrovascular haemorrhage, bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or any disease or condition with haemorrhagic tendencies (e.g. cerebral aneurysm, dissecting aorta, central nervous system (CNS) trauma, retinopathy or nephrolithiasis)
- •Recent or contemplated diagnostic or therapeutic procedures with potential for uncontrollable bleeding (e.g. spinal puncture, lumbar block anaesthesia, surgery of CNS or eye or surgery resulting in large open surfaces) within 14 days before or after drug administration of this clinical trial
- •Chronic or relevant acute infections
Arms & Interventions
Dabigatran high dose in healthy subjects
healthy subjects with a creatinine clearance of \>80 mL/m
Intervention: Dabigatran etexilate high dose
Dabigatran high dose in mild renal impairment
patients with a creatinine clearance of \>50 up to 80 mL/min
Intervention: Dabigatran etexilate high dose
Dabigatran high dose in moderate renal impairment
patients with a creatinine clearance of \>30 up to 50 mL/min
Intervention: Dabigatran etexilate high dose
Dabigatran high dose in severe renal impairment
patients with a creatinine clearance of up to 30 mL/min
Intervention: Dabigatran etexilate high dose
Dabigatran low dose in haemodialysis patients
patients requiring haemodialysis
Intervention: Dabigatran etexilate low dose
Outcomes
Primary Outcomes
AUC0-infinity (area under the concentration time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
Cmax (maximum concentration of the analyte in plasma)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
CL/F (apparent clearance of the analyte in the plasma after extravascular administration)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
international normalized ratio (INR)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
activated partial thromboplastin time (aPTT)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
Ecarin clotting time (ECT)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
thrombin time (TT)
Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients
Secondary Outcomes
- 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)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2, time interval to be determined)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- tmax (time from dosing to the maximum concentration of the analyte in plasma, oral administration only)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- λz (terminal rate constant in plasma)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- t1/2 (terminal half-life of the analyte in plasma)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- MRTpo (mean residence time of the analyte in the body after p.o. administration)(pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h after administration, additional 96 h in subjects with severe renal impairment and dialysis patients)
- Plasma protein binding of dabigatran(within 1 h before study drug administration)
- fe0-72 (fraction of administered drug excreted unchanged in urine from time point 0 to 72 h)(pre-dose over 12 hours and post dose in fractions of 0 - 12, 12 - 24, 24 - 48, and 48-72 h, additional until 96 h in subjects with severe renal impairment)
- Changes from baseline in pulse rate(Day 4, Day 5 in patients with renal impairment)
- Changes from baseline in routine laboratory(Day 4, Day 5 in patients with renal impairment)
- Occurrence of adverse events(up to day 4, up to day 5 in patients with renal impairment)
- Ae0-72 (amount of analyte that is eliminated in urine from the time interval 0 to 72 h)(pre-dose over 12 hours and post dose in fractions of 0 - 12, 12 - 24, 24 - 48, and 48-72 h, additional until 96 h in subjects with severe renal impairment)
- CLR,0-72 (renal clearance of the analyte in plasma from the time point 0 h until the timepoint 72 h)(pre-dose over 12 hours and post dose in fractions of 0 - 12, 12 - 24, 24 - 48, and 48-72 h, additional until 96 h in subjects with severe renal impairment)
- Assessment of tolerability on a 4-point scale(Day 4, Day 5 in patients with renal impairment)
- Changes from baseline in systolic and diastolic blood pressure(Day 4, Day 5 in patients with renal impairment)
- Changes from baseline in ECG(Day 4, Day 5 in patients with renal impairment)