Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate in Patients With and Without Renal Impairment

Study Overview
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Brief Summary
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To assess the effect of different degrees of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran etexilate administered orally.

Official Title
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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

Conditions
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Renal Insufficiency

Intervention / Treatment
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* Drug: Dabigatran etexilate high dose
* Drug: Dabigatran etexilate low dose


Participation Criteria
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Eligibility Criteria
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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 History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator For women with childbearing potential: no reliable contraception (accepted methods are intra uterine device, hormonal contraceptives, bilateral tubal ligation, hysterectomy, condoms) or pregnancy (known or detected by a positive pregnancy test) or breast feeding period Intake of drugs with a long half-life (>24 hours) (<1 month prior to administration or during the trial) Use of any drugs, within 14 days prior to administration or during the trial Participation in another trial with an investigational drug (<2 months prior to drug administration or during trial) Drug abuse Blood donation or loss >400 mL, <1 month prior to administration or during the trial Excessive physical activities <5 days prior to administration of study drug or during trial Clinically relevant laboratory abnormalities Renally impaired subjects (groups 2, 3, 4 and 5) who met any of the following criteria were not be entered into this trial: Moderate and severe concurrent liver function impairment (e.g. due to hepatorenal syndrome) Clinically relevant gastrointestinal, 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 values for PT, TT, aPTT and thrombocytes considered by the investigator or one of the co-investigators to be clinically relevant 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, CNS trauma, retinopathy, nephrolithiasis) considered by the investigator or one of the co-investigators to be clinically relevant 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 History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator For women with childbearing potential: no reliable contraception (accepted methods are intra-uterine device, hormonal contraceptives, bilateral tubal ligation, hysterectomy or condoms) or pregnancy (known or detected by a positive pregnancy test) or breast-feeding period Participation in another trial with an investigational drug (<2 months prior to administration or during trial) Drug abuse Blood donation or loss >400 mL, <1 month prior to administration or during the trial Excessive physical activities < 5 days prior to administration of study drug or during trial Clinically relevant laboratory abnormalities except those values typical for renally impaired patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran high dose in healthy subjects<br>healthy subjects with a creatinine clearance of >80 mL/m | Drug: Dabigatran etexilate high dose<br> <br> |
| Experimental: Dabigatran high dose in mild renal impairment<br>patients with a creatinine clearance of >50 up to 80 mL/min | Drug: Dabigatran etexilate high dose<br> <br> |
| Experimental: Dabigatran high dose in moderate renal impairment<br>patients with a creatinine clearance of >30 up to 50 mL/min | Drug: Dabigatran etexilate high dose<br> <br> |
| Experimental: Dabigatran high dose in severe renal impairment<br>patients with a creatinine clearance of up to 30 mL/min | Drug: Dabigatran etexilate high dose<br> <br> |
| Experimental: Dabigatran low dose in haemodialysis patients<br>patients requiring haemodialysis | Drug: Dabigatran etexilate low dose<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-infinity (area under the concentration time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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) |  | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Plasma protein binding of dabigatran |  | within 1 h before study drug administration | 
| Changes from baseline in pulse rate |  | 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 | 
| 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 | 
| Assessment of tolerability on a 4-point scale |  | Day 4, Day 5 in patients with renal impairment |