Pharmacokinetics of Empagliflozin (BI 10773) in Patients With Impaired Liver Function

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01111318
First received: April 26, 2010
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

The main objective of this study is to assess the effect of mild, moderate and severe hepatic impairment on the pharmacokinetics, safety and tolerability of BI 10773 following oral administration of BI 10773 as a single dose.


Condition Intervention Phase
Hepatic Insufficiency
Healthy
Drug: BI 10773
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinetics, Safety and Tolerability of BI 10773 50 mg Single Dose in Male and Female Subjects With Different Degrees of Liver Impairment (Child-Pugh Classification A, B and C) as Compared to Male and Female Healthy Subjects (a Non-blinded, Parallel Group Study of Phase I)

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Area Under the Curve 0 to Infinity (AUC0-∞) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity.

    The standard deviation is actually the coefficient of variation. The 'measured values' show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.


  • Maximum Measured Concentration (Cmax) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Maximum measured concentration of empagliflozin (empa) in plasma.

    The standard deviation is actually the coefficient of variation. The 'measured values' show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.



Secondary Outcome Measures:
  • Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration. ] [ Designated as safety issue: No ]

    Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the time of the last quantifiable data point.

    The standard deviation is actually the coefficient of variation.


  • Time From Dosing to Maximum Concentration (Tmax) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration. ] [ Designated as safety issue: No ]
    Time from dosing to maximum concentration of empagliflozin (empa) in plasma.

  • Terminal Rate Constant (λz) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Terminal rate constant in plasma.

    The standard deviation is actually the coefficient of variation.


  • Terminal Half-Life (t1/2) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Terminal half-life of empagliflozin (empa) in plasma.

    The standard deviation is actually the coefficient of variation.


  • Mean Residence Time (MRTpo) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Mean residence time of empagliflozin (empa) in the body.

    The standard deviation is actually the coefficient of variation.


  • Apparent Clearance After Extravascular Administration (CL/F) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Apparent clearance of empagliflozin (empa) in the plasma after extravascular administration.

    The standard deviation is actually the coefficient of variation.


  • Apparent Volume of Distribution During the Terminal Phase (Vz/F) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Apparent volume of distribution during the terminal phase (λz).

    The standard deviation is actually the coefficient of variation.


  • Amount of Empagliflozin That is Eliminated in Urine (Ae0-96) [ Time Frame: Pre-dose and time intervals 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h and 72-96h after drug administration ] [ Designated as safety issue: No ]

    Amount of empagliflozin (empa) that is eliminated in urine over the time interval 0 to 96 hours.

    The standard deviation is actually the coefficient of variation.


  • Fraction of Empagliflozin Excreted Unchanged in Urine (fe0-96)) [ Time Frame: Pre-dose and time intervals 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h and 72-96h after drug administration ] [ Designated as safety issue: No ]

    Fraction of empagliflozin (empa) excreted unchanged in urine from time points 0 to 96 hours.

    The standard deviation is actually the coefficient of variation.


  • Renal Clearance After Extravascular Administration (CL R) [ Time Frame: Pre-dose and 20minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h, 72h and 96h after drug administration ] [ Designated as safety issue: No ]

    Renal clearance of empagliflozin (empa) in plasma after extravascular administration.

    The standard deviation is actually the coefficient of variation.


  • Urinary Glucose Excretion (UGE) [ Time Frame: Pre-dose and time intervals 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h and 72-96h after drug administration ] [ Designated as safety issue: No ]

    Urinary glucose excretion, this endpoint was measured using Ae0-96.

    The standard deviation is actually the coefficient of variation.


  • Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Clinical Laboratory Tests and Assessment of Tolerability by the Investigator [ Time Frame: Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days ] [ Designated as safety issue: No ]
    Clinically relevant abnormalities for physical examination, vital signs, ECG, clinical laboratory tests and assessment of tolerability by the investigator. New abnormal findings or worsening of baseline conditions were reported as Adverse Events (AE).


Enrollment: 36
Study Start Date: July 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BI 10773
50 mg single dose
Drug: BI 10773
2 tablets BI 10773 25 mg single dose

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

Healthy males and females. Hepatically impaired male and female subjects. Age: 18 - 75 years, BMI: 18-34 kg/m2 Creatinine clearance >80 mL/min (except for patients with severe hepatic impairment, see exclusion criteria.

Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation.

Exclusion criteria:

Healthy subjects (group 1)

  1. Significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders as judged by the investigator.
  2. Relevant gastrointestinal tract surgery.
  3. Diseases of the central nervous system or psychiatric disorders or relevant neurological disorders.
  4. History of relevant orthostatic hypotension, fainting spells or blackouts; systolic blood pressure < 100 or > 160 mm Hg, diastolic blood pressure < 60 or > 100 mm Hg, pulse rate < 50 or > 100 1/min.
  5. Chronic or relevant acute infections.
  6. History of allergy/hypersensitivity.
  7. Intake of drugs with a long half-life (>24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial.
  8. Use within 10 days prior to administration or during the trial of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation
  9. Participation in another trial with an investigational drug within 2 months after a multiple dose study or within 1 month after a single dose study.
  10. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day).
  11. Inability to refrain from smoking when confined to the study site on trial days.
  12. Alcohol abuse, drug abuse.
  13. Veins unsuited for iv puncture on either arm.
  14. Blood donation (more than 100 mL within four weeks prior to administration or during the trial).
  15. Excessive physical activities (within 48 hours prior to trial or during the trial).
  16. Any laboratory value outside the reference range that is of clinical relevance.
  17. Inability to comply with dietary regimen of study centre.
  18. Subjects not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

    Hepatically impaired subjects (group 2-4):

  19. Decompensated gastrointestinal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders.
  20. For patients with severe liver impairment (Child-Pugh C): Severe concurrent renal dysfunction (e.g., due to hepato-renal syndrome) and a creatinine clearance <40mL/min.
  21. Relevant gastrointestinal tract surgery.
  22. Diseases of the central nervous system or psychiatric disorders or relevant neurological disorders.
  23. Chronic or relevant acute infections.
  24. History of allergy/hypersensitivity.
  25. Intake of drugs with a long half-life (>24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial.
  26. Use within 10 days prior to administration or during the trial of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation. Co-medication known to inhibit or induce P-glycoprotein (such as quinidine, cyclosporine, amiodarone) is not allowed. In dubious cases, a case by case decision will be made after consultation with the sponsor.
  27. Participation in another trial with an investigational drug within 2 months after a multiple dose study or within 1 month after a single dose study.
  28. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day).
  29. Inability to refrain from smoking when confined to the study site on trial days.
  30. Alcohol abuse, Drug abuse.
  31. Blood donation (more than 100 mL within four weeks prior to administration or during the trial).
  32. Excessive physical activities (within 48 hours prior to trial or during the trial).
  33. Clinically relevant laboratory abnormalities.
  34. Inability to comply with dietary regimen of study centre.
  35. Subjects not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions

    For female subjects of all groups:

  36. Pregnancy
  37. Positive pregnancy test
  38. No adequate contraception during the study and until 2 months after study completion.
  39. Lactation period.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01111318

Locations
Romania
1245.13.40001 Boehringer Ingelheim Investigational Site
Timisoara, Romania
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01111318     History of Changes
Other Study ID Numbers: 1245.13, 2009-017202-36
Study First Received: April 26, 2010
Results First Received: May 16, 2014
Last Updated: May 16, 2014
Health Authority: Romania: National Medicines Agency
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on July 22, 2014