Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Single and Multiple Doses of Linagliptin Tablets in Patients With Different Degrees of Renal Impairment in Comparison to Subjects With Normal Renal Function

NCT02191228 | Completed Phase 1

• 1 other identifier: 1218.26
• Study Type: interventional
• Target: 51
• Locations: 0 countries
• Sites: N/A

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)

Conditions

Renal Insufficiency

Outcome Measures

Primary Outcomes (4)

• 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

  up to 480 hours

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

  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

  up to 24 hours

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

  up to 264 hours

Secondary Outcomes (22)

• 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

• 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

• 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

Study Arms (7)

Group 1

EXPERIMENTAL

Linagliptin in subjects with normal renal function

Drug: Linagliptin - Multiple dose

Group 2

EXPERIMENTAL

Linagliptin in patients with mild renal insufficiency (RI)

Drug: Linagliptin - Multiple dose

Group 3

EXPERIMENTAL

Linagliptin in patients with moderate RI

Drug: Linagliptin - Multiple dose

Group 4

EXPERIMENTAL

Linagliptin in patients with severe RI

Drug: Linagliptin - single dose

Group 5

EXPERIMENTAL

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

Drug: Linagliptin - single dose

Group 6

EXPERIMENTAL

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

Drug: Linagliptin - Multiple dose

Group 7

EXPERIMENTAL

Linagliptin in patients with normal renal function and T2DM

Drug: Linagliptin - Multiple dose

Interventions

Linagliptin - single dose DRUG

Group 4; Group 5

Linagliptin - Multiple dose DRUG

Group 1; Group 2; Group 3; Group 6; Group 7

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• Inability to refrain from smoking when confined to the study site on trial days
• Alcohol abuse (more than 60 g/day in males or more than 40 g/day in females)
• Drug abuse, in the investigator's judgment, based on review of the participant's history and urine screening for abused substances
• Veins unsuited for intravenous puncture on either arm (e.g. veins which were difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture)
• Blood donation (more than 100 mL within 4 weeks prior to administration of study medication or during the trial)

Sponsors & Collaborators

• Boehringer Ingelheim: lead

MeSH Terms

Conditions

Renal Insufficiency

Interventions

Linagliptin

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinazolines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2014
• First Posted: July 16, 2014
• Study Start: April 1, 2008
• Primary Completion: February 1, 2010
• Last Updated: July 16, 2014

Record last verified: 2014-06