Clinical Trials/NCT02191228

NCT02191228

Completed

Phase 1

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Single and Multiple 5 mg Doses of Linagliptin Tablets in Patients With Different Degrees of Renal Impairment in Comparison to Subjects With Normal Renal Function in a Monocentric, Open, Parallel-group, Phase I Trial

Boehringer Ingelheim0 sites51 target enrollmentApril 2008

ConditionsRenal Insufficiency

InterventionsLinagliptin - Multiple dose Linagliptin - single dose

Overview

Phase: Phase 1
Intervention: Linagliptin - Multiple dose
Conditions: Renal Insufficiency
Sponsor: Boehringer Ingelheim
Enrollment: 51
Primary Endpoint: AUCτ,ss (area under the concentration time curve of the analyte in plasma over the time interval from 0 to 24h after the last dose at steady state) - multiple dose groups
Status: Completed
Last Updated: 11 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Similar Trials

Overview

Brief Summary

The main objective of this study was to assess the effect of normal and impaired renal function on the safety, pharmacokinetics, and pharmacodynamics of linagliptin following oral administration of 5 mg daily for 7 days (Groups 1 to 3), 5 mg daily for 10 days (Groups 6 and 7), or as a single dose (Groups 4 and 5)

Registry

clinicaltrials.gov

Start Date

April 2008

End Date

February 2010

Last Updated

11 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Boehringer Ingelheim

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Male or female subjects with normal renal function, defined as a Creatinine Clearance (CrCl) of \>80 mL/min on screening (Group 1) , or male or female patients with Type 2 diabetes mellitus (T2DM) and normal renal function, defined as a CrCl of \>80 mL/min on screening (Group 7)
•Male or female patients with Renal impairment (RI), determined by the value of CrCl on Screening estimated according to the Cockcroft-Gault formula. Patients were classified into groups by their CrCl values:
•Mild RI: CrCl\>50 to ≤80 mL/min (Group 2)
•Moderate RI: CrCl\>30 to ≤50 mL/min (Group 3)
•Severe RI: CrCl≤30 mL/min (Group 4)
•End-stage renal disease (ESRD): CrCl≤30 mL/min, requiring hemodialysis (Group 5)
•T2DM and severe RI: CrCl≤30 mL/min (Group 6)
•Age 18 to 80 years
•BMI 18 to 40 kg/m2, and minimum body mass of at least 45 kg for females
•Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation

Exclusion Criteria

•Participants (with or without RI) who met any of the following criteria were not included in this trial:
•Relevant gastrointestinal tract surgery (except appendectomy, cholecystectomy, or herniotomy)
•Diseases of the central nervous system, such as epilepsy, seizures, relevant neurological disorders, or psychiatric 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 were deemed relevant to the trial as judged by the investigator
•Intake of drugs with a long half-life (\>24 h) within at least one month prior to study start, or planned intake of study medication within ≤10 half-lives of administration of another medication. Medications that patients with RI were currently taking for treatment of renal disease were not included under this criterium.
•Use of medications during the trial or within 10 days prior to administration of study medication that might reasonably influence the results of the trial, based on knowledge at the time of protocol preparation. Co-medications known to inhibit or induce P-glycoprotein or CYP3A were not allowed. Inhibitors of P-glycoprotein or CYP3A include protease inhibitors (such as ritonavir, lopinavir, nelfinavir); azole antimycotics, (itraconazole, ketoconazole, miconazole); macrolide antibiotics, (clarithromycin, erythromycin); amiodarone, cimetidine, diltiazem, fluvoxamine, mibefradil, nefazodone, verapamil, tacrolimus, quinidine, reserpine, and cyclosporine A. Inducers of P-gp or CYP3A include carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort and troglitazone. In uncertain cases, a case-by-case decision was made after consultation with the sponsor.
•Participation in a previous trial with an investigational drug within 2 months of study start if the previous trial was a multiple dose study, or within 1 month of study start if the previous trial was a single dose study
•Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)

Arms & Interventions

Group 1

Linagliptin in subjects with normal renal function

Intervention: Linagliptin - Multiple dose

Group 2

Linagliptin in patients with mild renal insufficiency (RI)

Intervention: Linagliptin - Multiple dose

Group 3

Linagliptin in patients with moderate RI

Intervention: Linagliptin - Multiple dose

Group 4

Linagliptin in patients with severe RI

Intervention: Linagliptin - single dose

Group 5

Linagliptin in patients with end-stage renal disease (ESRD)

Intervention: Linagliptin - single dose

Group 6

Linagliptin in patients with severe RI and Type 2 diabetes mellitus (T2DM)

Intervention: Linagliptin - Multiple dose

Group 7

Linagliptin in patients with normal renal function and T2DM

Intervention: Linagliptin - Multiple dose

Outcomes

Primary Outcomes

AUCτ,ss (area under the concentration time curve of the analyte in plasma over the time interval from 0 to 24h after the last dose at steady state) - multiple dose groups

Time Frame: up to 480 hours

Cmax,ss (maximum concentration of the analyte in plasma at steady state) - multiple dose groups

Time Frame: up to 480 hours

AUC0-24 (area under the concentration time curve of the analyte in plasma over the time interval from 0 to 24h after the first dose) - single dose groups

Time Frame: up to 24 hours

Cmax (maximum concentration of the analyte in plasma) - single dose groups

Time Frame: up to 264 hours

Secondary Outcomes

C24,(ss) (concentration of the analyte in plasma at steady state after administration of the first or last dose at the end of the dosing interval) - multiple dose groups(up to 480 hours)
tmax,(ss) (time from last dosing to maximum concentration of the analyte in plasma after the first dose or at steady state) - multiple dose groups(up to 480 hours)
λz,(ss) (terminal rate constant in plasma after single dose/at steady state) - multiple dose groups(up to 480 hours)
t1/2,(ss) (terminal half-life of the analyte in plasma after single dose/at steady state) - multiple dose groups(up to 480 hours)
MRTpo,(ss) (mean residence time of the analyte in the body after single dose/at steady state after oral administration) - multiple dose groups(up to 480 hours)
CL/F,(ss) (apparent clearance of the analyte in the plasma after extravascular administration after single dose/at steady state) - multiple dose groups(up to 480 hours)
Vz/F,(ss) (apparent volume of distribution during the terminal phase λz after single dose/at steady state following extravascular administration) - multiple dose groups(up to 480 hours)
AUC0-∞ (area under the concentration time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity after single dose in severely impaired or end stage renal disease (ESRD) patients)(up to 264 hours)
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 after single dose in severely impaired or ESRD patients)(up to 264 hours)
%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 after single dose in severely impaired or ESRD patients)(up to 264 hours)
Assessment of Plasma protein binding(predose Day 1)
Model-derived AUCτ,ss in severely impaired or ESRD patients(up to 264 hours)
Model-derived Cmax,ss in severely impaired or ESRD patients(up to 264 hours)
Change in Dipeptidyl peptidase IV (DPP-4) activity in plasma(up to 480 hours)
Number of patients with abnormal findings in physical examination(up to day 32)
Number of patients with clinically significant changes in vital signs(up to day 32)
Number of patients with abnormal changes 12-lead ECG (electrocardiogram)(up to day 32)
Number of patients with abnormal changes in laboratory parameters(up to day 32)
Number of patients with adverse events(up to 53 days)
Assessment of tolerability by investigator on a 4-point scale(up to 480 hours)
AUC0-24 (area under the concentration time curve of the analyte in plasma over the time interval from 0 to 24h after the first dose) - multiple dose groups(up to 24 hours)
Cmax (maximum concentration of the analyte in plasma) - multiple dose groups(up to 480 hours)