Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of BI 10773 in Type II Diabetes Patients With Different Degrees of Renal Impairment

Study Overview
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Brief Summary
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Assessment of the effect of normal and impaired kidney function on the pharmacokinetics, pharmacodynamics and safety of BI 10773

Official Title
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Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of a Single 50 mg Dose of BI 10773 in Patients With Different Degrees of Renal Impairment in Comparison to Subjects With Type 2 Diabetes and Normal Renal Function in a Monocentric, Open-label, Parallel-group, Phase 1 Trial

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI 10773
* Drug: BI 10773
* Drug: BI 10773
* Drug: BI 10773
* Drug: BI 10773


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female subjects with type 2 diabetes Renally impaired male or female subjects Age 18 - 75 years BMI 18 - 34 kg/m2, at least 45 kg for females (Body Mass Index) Signed and dated written informed consent Exclusion criteria: Significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders as judged by the investigator. Relevant gastrointestinal tract surgery Diseases of the central nervous system (such as epilepsy, seizures) or psychiatric disorders or relevant neurological disorders 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 Chronic or relevant acute infections History of allergy/hypersensitivity (including drug allergies) that are deemed relevant to the trial as judged by the investigator 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 or CYP3A is not allowed. Inhibitors of P-glycoprotein or CYP3A (cytochrom P3A) are e.g. protease inhibitors, (e.g. ritonavir, lopinavir nelfinavir) azole antimycotics, (itraconazole, ketoconazole, miconazole) macrolid antibiotics, (clarithromycin, erythromycin) amiodarone, cimetidine, diltiazem, fluvoxamine, mibefradil, nefazodone, verapamil, tacrolimus, quinidine, reserpine, cyclosporine A Inducers of P-gp or CYP3A are e.g. carbamazepine, phenobarbital, phenytoin, rifabutin, ri-fampin, St. John's wort, troglitazone. In dubious cases, a case by case decision will be made after consultation with the sponsor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 10773 / Group 2<br>Single Dose Administration (type 2 diabetes and mild renal impairment) | Drug: BI 10773<br>* oral administration<br>|
| Experimental: BI 10773 / Group 3<br>Single Dose Administration (type 2 diabetes and moderate renal impairment) | Drug: BI 10773<br>* oral administration<br>|
| Experimental: BI 10773 / Group 4<br>Single Dose Administration (severe renal impairment 8) | Drug: BI 10773<br>* oral administration<br>|
| Experimental: BI 10773 / Group 5<br>Single Dose Administration (kidney failure) | Drug: BI 10773<br>* oral administration<br>|
| Experimental: BI 10773 / Group 1<br>Single Dose Administration (type 2 diabetes and normal renal function) | Drug: BI 10773<br>* oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ (Area Under the Concentration Time Curve of the Analyte in Plasma Over the Time Interval From 0 to Infinity) | Area under the concentration time curve of the analyte in plasma over the time interval from 0 to infinity. The areas under the curve were calculated using the linear up/log down algorithm. If a drug concentration was equal to or higher than the preceding concentration, the linear trapezoidal method was used. If the drug concentration was smaller than the preceding concentration, the logarithmic method was used. | 1 hour (h) before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Cmax (Maximum Concentration of the Analyte in Plasma) | Maximum concentration of Empagliflozin in plasma | 1 hour (h) before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Concentration of the Analyte in Plasma | Time from last dosing to maximum concentration of Empagliflozin in plasma (tmax) | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Half-life and Mean Residence Time of the Analyte in Plasma | Terminal half-life of Empagliflozin (t1/2) and Mean residence time of Empagliflozin in the body | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Terminal Rate Constant in Plasma | Terminal rate constant in plasma (Lz) | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Apparent Clearance of the Analyte in the Plasma After Extravascular Administration | Apparent clearance of the analyte in the plasma after extravascular administration | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Apparent Volume of Distribution During the Terminal Phase Lz | Apparent volume of distribution during the terminal phase Lz | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point. The areas under the curve were calculated using the linear up/log down algorithm. If a drug concentration was equal to or higher than the preceding concentration, the linear trapezoidal method was used. If the drug concentration was smaller than the preceding concentration, the logarithmic method was used. | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Ae0-96 (Amount of Analyte That is Eliminated in Urine Over the Time Interval 0 to 96 h) | Amount of analyte that is eliminated in urine over the time interval 0-96 hours. | 24-0 h before drug administration and 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 hours after drug administration | 
| fe0-96 (Fraction of Analyte Excreted Unchanged in Urine From Time Points 0 to 96 Hours) | Fraction of analyte excreted unchanged in urine from time point 0-96 hours. | 24-0 h before drug administration and 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 hours after drug administration | 
| Renal Clearance of the Analyte in Plasma After Extravascular Administration | Renal Clearance of the Analyte in Plasma After Extravascular Administration for time interval 0-96 hours. | 24-0 h before drug administration and 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 hours after drug administration | 
| %AUCtz-∞ (Percentage of Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From the Time of the Last Quantifiable Data Point Extrapolated to Infinity) | Percentage of area under the concentration-time curve of the analyte in plasma over the time interval from the time of the last quantifiable data point extrapolated to infinity | 1 h before drug administration and 0:20, 0:40, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 14:00, 24:00, 36:00. 48:00, 72:00, 96:00 h after drug administration | 
| Plasma Protein Binding | Plasma protein binding is the percent of analyte binding to the plasma protein, pre-dose plasma samples were spiked with Empa 1000 nmol/L. The standard deviation is actually the coefficient of variation. | 1 h before drug administration and 1:30 and 3:00 h after drug administration | 
| Total Urinary Glucose Excretion (UGE) | Change from baseline in total urinary glucose excretion | 24-0 h before drug administration and 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 hours after drug administration (Interval 24-0 h before drug administration only for baseline UGE) | 
| Safety: Physical Examination, Vital Signs, ECG and Laboratory Measurements | Number of participants with clinically relevant findings in physical examination, Vital Signs, Clinically Significant Abnormalities in Electrocardiogram (ECG) and Significant Changes from Baseline Laboratory Measurements | Drug administration until end-of-study-examination, 5 days | 
| Assessment of Tolerability by Investigator | Tolerability was assessed by the investigator based on adverse events and the laboratory evaluation. | Drug administration until end-of-study-examination, 5 days |