Clinical trial NCT01111318: Pharmacokinetics of Empagliflozin (BI 10773) in Patients With Impaired Liver Function
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Insufficiency
Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2010-04-27
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Area Under the Curve 0 to Infinity (AUC0-∞)
timeFrame: 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
measure: Maximum Measured Concentration (Cmax)
timeFrame: 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 outcomes:
measure: Area Under the Curve 0 to Time of Last Quantifiable Data Point (AUC0-tz)
timeFrame: 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.
measure: Time From Dosing to Maximum Concentration (Tmax)
timeFrame: 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.
measure: Terminal Rate Constant (λz)
timeFrame: 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
measure: Terminal Half-Life (t1/2)
timeFrame: 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
measure: Mean Residence Time (MRTpo)
timeFrame: 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
measure: Apparent Clearance After Extravascular Administration (CL/F)
timeFrame: 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
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F)
timeFrame: 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
measure: Amount of Empagliflozin That is Eliminated in Urine (Ae0-96)
timeFrame: 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
measure: Fraction of Empagliflozin Excreted Unchanged in Urine (fe0-96))
timeFrame: 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
measure: Renal Clearance After Extravascular Administration (CL R)
timeFrame: 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
measure: Urinary Glucose Excretion (UGE)
timeFrame: 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
measure: Clinically Relevant Abnormalities for Physical Examination, Vital Signs, ECG, Clinical Laboratory Tests and Assessment of Tolerability by the Investigator
timeFrame: Drug administration until 4 days after drug administration or end-of-study visit, up to 19 days
Other outcomes:
Locations:
city: Timisoara
country: Romania
facility: 1245.13.40001 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: