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

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)

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.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency; Healthy
• Intervention / Treatment: Drug: BI 10773

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Romania
  • Timisoara, Romania
    • 1245.13.40001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 10773; 50 mg single dose	Drug: BI 10773; 2 tablets BI 10773 25 mg single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve 0 to Infinity (AUC0-∞)	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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.
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.
Terminal Rate Constant (λz)	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
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
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
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
Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Apparent volume of distribution during the terminal phase (λz). 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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: April 26, 2010
• First Submitted That Met QC Criteria: April 26, 2010
• First Posted (Estimate): April 27, 2010

Study Record Updates

• Last Update Posted (Estimate): June 13, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 1245.13; 2009-017202-36 (EudraCT Number: EudraCT)