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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT02191228
First received: July 15, 2014
Last updated: NA
Last verified: June 2014
History: No changes posted
  Purpose

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)


Condition Intervention Phase
Renal Insufficiency
Drug: Linagliptin - single dose
Drug: Linagliptin - Multiple dose
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • Cmax,ss (maximum concentration of the analyte in plasma at steady state) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Cmax (maximum concentration of the analyte in plasma) - single dose groups [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • λz,(ss) (terminal rate constant in plasma after single dose/at steady state) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • t1/2,(ss) (terminal half-life of the analyte in plasma after single dose/at steady state) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • MRTpo,(ss) (mean residence time of the analyte in the body after single dose/at steady state after oral administration) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • CL/F,(ss) (apparent clearance of the analyte in the plasma after extravascular administration after single dose/at steady state) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • Vz/F,(ss) (apparent volume of distribution during the terminal phase λz after single dose/at steady state following extravascular administration) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]
  • %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) [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]
  • Assessment of Plasma protein binding [ Time Frame: predose Day 1 ] [ Designated as safety issue: No ]
  • Model-derived AUCτ,ss in severely impaired or ESRD patients [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]
  • Model-derived Cmax,ss in severely impaired or ESRD patients [ Time Frame: up to 264 hours ] [ Designated as safety issue: No ]
  • Change in Dipeptidyl peptidase IV (DPP-4) activity in plasma [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • Number of patients with abnormal findings in physical examination [ Time Frame: up to day 32 ] [ Designated as safety issue: No ]
  • Number of patients with clinically significant changes in vital signs [ Time Frame: up to day 32 ] [ Designated as safety issue: No ]
  • Number of patients with abnormal changes 12-lead ECG (electrocardiogram) [ Time Frame: up to day 32 ] [ Designated as safety issue: No ]
  • Number of patients with abnormal changes in laboratory parameters [ Time Frame: up to day 32 ] [ Designated as safety issue: No ]
  • Number of patients with adverse events [ Time Frame: up to 53 days ] [ Designated as safety issue: No ]
  • Assessment of tolerability by investigator on a 4-point scale [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: up to 24 hours ] [ Designated as safety issue: No ]
  • Cmax (maximum concentration of the analyte in plasma) - multiple dose groups [ Time Frame: up to 480 hours ] [ Designated as safety issue: No ]

Enrollment: 51
Study Start Date: April 2008
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
Linagliptin in subjects with normal renal function
Drug: Linagliptin - Multiple dose
Experimental: Group 2
Linagliptin in patients with mild renal insufficiency (RI)
Drug: Linagliptin - Multiple dose
Experimental: Group 3
Linagliptin in patients with moderate RI
Drug: Linagliptin - Multiple dose
Experimental: Group 4
Linagliptin in patients with severe RI
Drug: Linagliptin - single dose
Experimental: Group 5
Linagliptin in patients with end-stage renal disease (ESRD)
Drug: Linagliptin - single dose
Experimental: Group 6
Linagliptin in patients with severe RI and Type 2 diabetes mellitus (T2DM)
Drug: Linagliptin - Multiple dose
Experimental: Group 7
Linagliptin in patients with normal renal function and T2DM
Drug: Linagliptin - Multiple dose

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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)
  • 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)
  • Excessive physical activities (within 48 h prior to start of the trial or during the trial)
  • Any laboratory value outside the reference range that was of clinical relevance (exceptions were in patients with RI who had abnormal renal function tests or deviations of clinical laboratory values that were related to renal impairment)
  • Inability to comply with the dietary regimen of study centre
  • Inability to understand and comply with protocol requirements, instructions and protocol-stated restrictions

For female patients

  • Pregnancy
  • Positive pregnancy test (human chorionic gonadotropin (β HCG) in urine))
  • No adequate contraception in women of childbearing potential (adequate contraception was considered to be sterilisation, use of an intrauterine device, or use of oral contraception along with a barrier method)
  • Lactation period

Subjects with normal renal function (Group 1) and subjects with T2DM and normal renal function (Group 7) who met the following criterium were not included in this trial:

  • Significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders as judged by the investigator

Patients with RI who met any of the following criteria were not included in this trial:

  • Moderate and severe concurrent liver function impairment (for example, due to hepatorenal syndrome)
  • Patients with significant diseases other than renal impairment were excluded. A significant disease was defined as a disease which in the opinion of the investigator put the patient at risk during participation in the study, could influence the results of the study, could influence the patient's ability to participate in the study, or was an unstable condition. Patients with diabetes (for Groups 1 to 5) or hypertension could be included in the trial if the disease was not significant according to these criteria.
  • Haemoglobin <8 g/dL, indicating severe anaemia of renal origin (use of erythropoietin was allowed to maintain haematocrit)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02191228     History of Changes
Other Study ID Numbers: 1218.26
Study First Received: July 15, 2014
Last Updated: July 15, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Linagliptin
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014