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

Healthy Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01111318
• Other study ID #: 1245.13
• Secondary ID: 2009-017202-36
• Status: Completed
• Phase: Phase 1
• First received: April 26, 2010
• Last updated: May 16, 2014
• Start date: July 2010

Study information

• Verified date: May 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Romania: National Medicines AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. primary completion date: November 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Healthy
• Hepatic Insufficiency

Intervention

Drug:
• BI 10773
2 tablets BI 10773 25 mg single dose

Locations

Country	Name	City	State
Romania	1245.13.40001 Boehringer Ingelheim Investigational Site	Timisoara

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Romania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Curve 0 to Infinity (AUC0-8)	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.	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	No
Primary	Maximum Measured Concentration (Cmax)	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.	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	No
Secondary	Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz)	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.	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.	No
Secondary	Time From Dosing to Maximum Concentration (Tmax)	Time from dosing to maximum concentration of empagliflozin (empa) in plasma.	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.	No
Secondary	Terminal Rate Constant (?z)	Terminal rate constant in plasma.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Terminal Half-Life (t1/2)	Terminal half-life of empagliflozin (empa) in plasma.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Mean Residence Time (MRTpo)	Mean residence time of empagliflozin (empa) in the body.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Apparent Clearance After Extravascular Administration (CL/F)	Apparent clearance of empagliflozin (empa) in the plasma after extravascular administration.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Apparent volume of distribution during the terminal phase (?z).; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Amount of Empagliflozin That is Eliminated in Urine (Ae0-96)	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.	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	No
Secondary	Fraction of Empagliflozin Excreted Unchanged in Urine (fe0-96))	Fraction of empagliflozin (empa) excreted unchanged in urine from time points 0 to 96 hours.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Renal Clearance After Extravascular Administration (CL R)	Renal clearance of empagliflozin (empa) in plasma after extravascular administration.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Urinary Glucose Excretion (UGE)	Urinary glucose excretion, this endpoint was measured using Ae0-96.; The standard deviation is actually the coefficient of variation.	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	No
Secondary	Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Clinical Laboratory Tests and Assessment of Tolerability by the Investigator	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).	Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days	No

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