Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate in Patients With Moderate Hepatic Impairment Compared to Subjects With Normal Hepatic Function

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of 150 mg Dabigatran Etexilate p.o. in Patients With Moderate Hepatic Impairment Compared to Subjects With Normal Hepatic Function in a Monocentric, Open, Parallel-group Design

Assessment of the effect of moderate liver impairment (Child-Pugh classification B) on the pharmacokinetics and pharmacodynamics of dabigatran after oral administration of dabigatran etexilate. Determination of safety and tolerability of dabigatran upon administration to hepatically impaired patients and healthy subjects (matched pairs)

Inclusion Criteria:

• Healthy age-, weight-, and sex-matched subjects determined by results of screening with normal hepatic function (group 1)
• Hepatically impaired subjects determined by results of screening classified as Child-Pugh B (group 2)
• 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
• Creatinine clearance >80 mL/min according to Cockcroft & Gault

Exclusion Criteria:

• Healthy subjects (Group 1) who met any of the following criteria should not be entered into this trial:

  • 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, herniotomy)
  • Clinically relevant diseases of the central nervous system
  • Relevant history of orthostatic hypotension, fainting spells or blackouts
  • 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, 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 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 the trial
  • Clinically relevant laboratory abnormalities
  • Veins unsuited for i.v. puncture and administration of prolonged infusions on either arm (e.g. veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture, etc.)

• Hepatically impaired subjects (Group 2) who met any of the following criteria should not be entered into this trial:

  • Moderate and severe concurrent renal function impairment (e.g., due to hepato-renal syndrome)
  • Clinically relevant gastrointestinal, respiratory, cardiovascular, metabolic, immunologic or hormonal disorders
  • Surgery of gastrointestinal tract (except appendectomy, cholecystectomy, herniotomy)
  • Clinically relevant diseases of the central nervous system
  • Relevant history of orthostatic hypotension, fainting spells or blackouts
  • 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 coinvestigators 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
  • 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
  • Use of any drugs which have an influence on the blood clotting within 14 days prior to administration or during the trial
  • Participation in another trial with an investigational drug (< 2 months prior to administration or during trial)
  • 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 the trial
  • Clinically relevant laboratory abnormalities (except for liver function tests according to Child-Pugh classification), constellation of blood clotting parameters according to the judgment of the investigator
  • Veins unsuited for i.v. puncture and administration of prolonged infusions on either arm (e.g. veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture, etc.)