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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01111318
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arm: 1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Insufficiency; Healthy	Drug: BI 10773	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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)
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Nov 1, 2010

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve 0 to Infinity (AUC0-∞) [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]

   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.

2. Maximum Measured Concentration (Cmax) [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 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

1. Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz) [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.]

   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.

2. Time From Dosing to Maximum Concentration (Tmax) [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 of empagliflozin (empa) in plasma.

3. Terminal Rate Constant (λz) [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 in plasma. The standard deviation is actually the coefficient of variation.

4. Terminal Half-Life (t1/2) [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 of empagliflozin (empa) in plasma. The standard deviation is actually the coefficient of variation.

5. Mean Residence Time (MRTpo) [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 of empagliflozin (empa) in the body. The standard deviation is actually the coefficient of variation.

6. Apparent Clearance After Extravascular Administration (CL/F) [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 of empagliflozin (empa) in the plasma after extravascular administration. The standard deviation is actually the coefficient of variation.

7. Apparent Volume of Distribution During the Terminal Phase (Vz/F) [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 (λz). The standard deviation is actually the coefficient of variation.

8. Amount of Empagliflozin That is Eliminated in Urine (Ae0-96) [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]

   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.

9. Fraction of Empagliflozin Excreted Unchanged in Urine (fe0-96)) [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 (empa) excreted unchanged in urine from time points 0 to 96 hours. The standard deviation is actually the coefficient of variation.

10. Renal Clearance After Extravascular Administration (CL R) [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]

    Renal clearance of empagliflozin (empa) in plasma after extravascular administration. The standard deviation is actually the coefficient of variation.

11. Urinary Glucose Excretion (UGE) [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]

    Urinary glucose excretion, this endpoint was measured using Ae0-96. The standard deviation is actually the coefficient of variation.

12. Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Clinical Laboratory Tests and Assessment of Tolerability by the Investigator [Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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):

1. Decompensated gastrointestinal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders.

2. 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.

3. Relevant gastrointestinal tract surgery.

4. Diseases of the central nervous system or psychiatric disorders or relevant neurological disorders.

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. 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.

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. Blood donation (more than 100 mL within four weeks prior to administration or during the trial).

14. Excessive physical activities (within 48 hours prior to trial or during the trial).

15. Clinically relevant laboratory abnormalities.

16. Inability to comply with dietary regimen of study centre.

17. Subjects not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions

For female subjects of all groups:

1. Pregnancy

2. Positive pregnancy test

3. No adequate contraception during the study and until 2 months after study completion.

4. Lactation period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1245.13.40001 Boehringer Ingelheim Investigational Site	Timisoara		Romania

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01111318
• Other Study ID Numbers: 1245.13; 2009-017202-36
• First Posted: Apr 27, 2010
• Last Update Posted: Jun 13, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Hepatic Insufficiency; Liver Failure; Empagliflozin

Study Results

Participant Flow

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Period Title: Overall Study
STARTED	12	8	8	8
COMPLETED	12	8	8	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Healthy	Mild	Moderate	Severe	Total
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.	Total of all reporting groups
Overall Participants	12	8	8	8	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.8 (9.2)	57.0 (6.9)	51.0 (8.5)	53.9 (9.6)	53.9 (8.6)
Sex: Female, Male (Count of Participants)
Female	8 66.7%	4 50%	3 37.5%	4 50%	19 52.8%
Male	4 33.3%	4 50%	5 62.5%	4 50%	17 47.2%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve 0 to Infinity (AUC0-∞)
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [nmol*h/L]	10800 (22.6)	13800 (38.6)	16100 (26.2)	19000 (27.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy, Mild
	Comments	Ratio calculated as mild divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	123.15
	Confidence Interval	(2-Sided) 90%; 98.89 to 153.36
	Parameter Dispersion	Type: Standard Deviation; Value: 29.0
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy, Moderate
	Comments	Ratio calculated as moderate divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	146.97
	Confidence Interval	(2-Sided) 90%; 118.02 to 183.02
	Parameter Dispersion	Type: Standard Deviation; Value: 29.0
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy, Severe
	Comments	Ratio calculated as severe divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	174.70
	Confidence Interval	(2-Sided) 90%; 140.29 to 217.55
	Parameter Dispersion	Type: Standard Deviation; Value: 29.0
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

2. Primary Outcome

Title	Maximum Measured Concentration (Cmax)
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [nmol/L]	1370 (33.9)	1430 (36.8)	1660 (26.4)	1970 (22.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Healthy, Mild
	Comments	Ratio calculated as mild divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	103.81
	Confidence Interval	(2-Sided) 90%; 82.29 to 130.95
	Parameter Dispersion	Type: Standard Deviation; Value: 30.7
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Healthy, Moderate
	Comments	Ratio calculated as moderate divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	123.31
	Confidence Interval	(2-Sided) 90%; 97.74 to 155.55
	Parameter Dispersion	Type: Standard Deviation; Value: 30.7
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Healthy, Severe
	Comments	Ratio calculated as severe divided by healthy
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	No formal testing, investigation of relative bioavailability
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	148.41
	Confidence Interval	(2-Sided) 90%; 117.65 to 187.23
	Parameter Dispersion	Type: Standard Deviation; Value: 30.7
	Estimation Comments	Standard deviation is actually the geometric coefficient of variation

3. Secondary Outcome

Title	Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz)
Description	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 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.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [nmol*h/L]	10700 (22.6)	13700 (38.4)	15800 (25.7)	18600 (23.9)

4. Secondary Outcome

Title	Time From Dosing to Maximum Concentration (Tmax)
Description	Time from dosing to maximum concentration of empagliflozin (empa) in plasma.
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.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Median (Full Range) [h]	2.00 (50.1)	1.50 (73.2)	2.00 (64.4)	1.50 (48.2)

5. Secondary Outcome

Title	Terminal Rate Constant (λz)
Description	Terminal rate constant in plasma. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [1/h]	0.0414 (41.6)	0.0404 (23.5)	0.0454 (28.9)	0.0506 (41.1)

6. Secondary Outcome

Title	Terminal Half-Life (t1/2)
Description	Terminal half-life of empagliflozin (empa) in plasma. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [h]	19.9 (43.1)	18.1 (25.9)	17.1 (45.9)	17.7 (67.4)

7. Secondary Outcome

Title	Mean Residence Time (MRTpo)
Description	Mean residence time of empagliflozin (empa) in the body. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [h]	13.2 (31.3)	14.4 (22.9)	15.5 (37.2)	15.7 (43.0)

8. Secondary Outcome

Title	Apparent Clearance After Extravascular Administration (CL/F)
Description	Apparent clearance of empagliflozin (empa) in the plasma after extravascular administration. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [mL/min]	179 (23.9)	150 (34.4)	124 (30.7)	103 (23.0)

9. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase (Vz/F)
Description	Apparent volume of distribution during the terminal phase (λz). The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [L]	298 (39.5)	237 (45.5)	173 (35.0)	144 (46.7)

10. Secondary Outcome

Title	Amount of Empagliflozin That is Eliminated in Urine (Ae0-96)
Description	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.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [nmol]	18400 (26.5)	16900 (20.6)	18500 (35.0)	22500 (23.5)

11. Secondary Outcome

Title	Fraction of Empagliflozin Excreted Unchanged in Urine (fe0-96))
Description	Fraction of empagliflozin (empa) excreted unchanged in urine from time points 0 to 96 hours. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [percentage of empagliflozin]	16.6 (26.5)	15.2 (20.6)	16.7 (35.0)	20.3 (23.5)

12. Secondary Outcome

Title	Renal Clearance After Extravascular Administration (CL R)
Description	Renal clearance of empagliflozin (empa) in plasma after extravascular administration. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Mean (Standard Deviation) [mL/min]	28.7 (30.3)	23.7 (48.0)	19.9 (36.8)	21.3 (37.1)

13. Secondary Outcome

Title	Urinary Glucose Excretion (UGE)
Description	Urinary glucose excretion, this endpoint was measured using Ae0-96. The standard deviation is actually the coefficient of variation.
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all subjects who were documented to have taken the investigational treatment, who provided at least one observation for at least one primary PK endpoint, without important protocol violations relevant to the evaluation of PK, provided no vomiting occurred at or before two times median tmax.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	7	8	8
Mean (Standard Deviation) [mg]	86600 (34.8)	81000 (26.7)	79700 (67.9)	79800 (45.6)

14. Secondary Outcome

Title	Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Clinical Laboratory Tests and Assessment of Tolerability by the Investigator
Description	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).
Time Frame	Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days

Outcome Measure Data

Analysis Population Description

Treated Set (TS) included all subjects who had been dispensed study medication and were documented to have taken the investigational treatment.

Arm/Group Title	Healthy	Mild	Moderate	Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
Measure Participants	12	8	8	8
Investigations: Electrocardiogram abnormal	2 16.7%	0 0%	0 0%	0 0%
Investigations: Nitrite urine present	0 0%	0 0%	0 0%	1 12.5%

Adverse Events

Time Frame	Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days
Arm/Group Title	Healthy		Mild		Moderate		Severe
Arm/Group Description	Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for healthy subjects with normal liver function who matched the hepatically impaired subjects with regard to age and weight.		Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with mild liver impairment defined by Child-Pugh class A.		Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with moderate liver impairment defined by Child-Pugh class B.		Single oral dose of empagliflozin (empa) 50mg (2 tablets of 25mg) following an overnight fast, for patients with severe liver impairment defined by Child-Pugh class C.
All Cause Mortality
	Healthy		Mild		Moderate		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Healthy		Mild		Moderate		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Healthy		Mild		Moderate		Severe
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		0/8 (0%)		3/8 (37.5%)		2/8 (25%)
Cardiac disorders
Myocardial ischaemia	0/12 (0%)		0/8 (0%)		2/8 (25%)		0/8 (0%)
Gastrointestinal disorders
Constipation	4/12 (33.3%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)
Toothache	1/12 (8.3%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
General disorders
Pyrexia	0/12 (0%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)
Infections and infestations
Asymptomatic bacteriuria	0/12 (0%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)
Investigations
Electrocardiogram abnormal	2/12 (16.7%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Nitrite urine present	0/12 (0%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)
Musculoskeletal and connective tissue disorders
Back pain	1/12 (8.3%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Nervous system disorders
Headache	3/12 (25%)		0/8 (0%)		1/8 (12.5%)		0/8 (0%)
Renal and urinary disorders
Leukocyturia	0/12 (0%)		0/8 (0%)		0/8 (0%)		1/8 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.