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

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

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

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: BI 10773

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Kiel, Germany
    • 1245.12.1 Boehringer Ingelheim Investigational Site
  • Neuss, Germany
    • 1245.12.2 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Male and female subjects with type 2 diabetes
2. Renally impaired male or female subjects
3. Age 18 - 75 years
4. BMI 18 - 34 kg/m2, at least 45 kg for females (Body Mass Index)
5. Signed and dated written informed consent

Exclusion criteria:

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 (such as epilepsy, seizures) 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 (including drug allergies) that are deemed relevant to the trial as judged by the investigator

7. 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.

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

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): December 1, 2009

Study Registration Dates

• First Submitted: July 15, 2013
• First Submitted That Met QC Criteria: July 22, 2013
• First Posted (Estimate): July 24, 2013

Study Record Updates

• Last Update Posted (Estimate): July 14, 2014
• Last Update Submitted That Met QC Criteria: July 11, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 1245.12; 2008-006086-86 (EudraCT Number: EudraCT)