Bioavailability of Combination Tablet BI 1356/Metformin Compared With Single BI 1356 and Metformin Administered Together to Healthy Male and Female Subjects

Relative Oral Bioavailability of a Fixed Dose Combination Tablet of BI 1356 2.5 mg / Metformin 1000 mg, Compared With Single BI 1356 2.5 mg and Metformin 1000 mg Tablets Administered Together to Healthy Male and Female Subjects in an Open, Randomised, Single-dose, Two-way Crossover, Phase I Trial

The objective was to assess the relative bioavailability of a pilot scale linagliptin 2.5 mg / metformin 1000 mg fixed dose combination (FDC) tablet in comparison with single tablets of linagliptin 2.5 mg and metformin 1000 mg administered together.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: BI 1356/metformin; Drug: BI 1356; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males and females based upon a complete medical history, including the physical examination, vital signs (Blood Pressure, Pulse Rate), 12-lead Electrocardiogram, clinical laboratory tests
• Age ≥18 and ≤ 55 years
• BMI ≥18.5 and ≤29.9 kg/m2 (Body Mass Index)
• Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation

Exclusion Criteria:

• Any finding of the medical examination deviating from normal and of clinical relevance. Repeated measurement of a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg
• Any evidence of a clinically relevant concomitant disease
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Surgery of the gastrointestinal tract (except appendectomy)
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
• Intake of drugs within one month or less than 10 half-lives of the respective drug prior to first study drug administration and during the trial except if a relevant interaction can be ruled out
• Participation in another trial with an investigational drug within two months prior to first study drug administration or during the trial
• Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day)
• Inability to refrain from smoking on pharmacokinetic study days
• Alcohol abuse (average consumption of more than 20 g/day in females and more than 30 g/day in males)
• Drug abuse
• Blood donation (more than 100 mL within four weeks prior to the start of study)
• Excessive physical activities (within one week prior to administration or during the trial)
• Any laboratory value outside the reference range that is of clinical relevance
• Inability to comply with dietary regimen of trial site
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 450 ms)
• A history of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

For female subjects:

• Positive pregnancy test, pregnancy or planning to become pregnant during the study or within 2 months after study completion
• No adequate contraception during the study and until 2 months after study completion, i.e. not any of the following: implants, injectables, combined oral contraceptives, IUD (intrauterine device), sexual abstinence for at least 1 month prior to enrolment, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent or surgically sterile will be asked to use an additional barrier method (e.g. condom, diaphragm with spermicide)
• Lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 1356/metformin	Drug: BI 1356/metformin; fixed dose combination tablet
Experimental: BI 1356 + Metformin	Drug: BI 1356; Drug: Metformin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AUC0-72 h (area under the concentration-time curve of BI 1356 in plasma over the time interval from 0 to 72 h)	up to 72 hours after administration
Cmax (maximum measured concentration of the analyte in plasma)	up to 168 hours after administration
AUC0-∞ (area under the concentration-time curve of metformin in plasma over the time interval from 0 to infinity)	up to 168 h after administration

Secondary Outcome Measures

Outcome Measure	Time Frame
tmax (time from dosing to maximum concentration of the analyte in plasma)	up to 168 hours after administration
λz (terminal elimination rate constant of the analyte in plasma)	up to 168 hours after administration
t1/2 (terminal half-life of the analyte in plasma)	up to 168 hours after administration
MRTpo (mean residence time of the analyte in the body after po administration)	up to 168 hours after administration
CL/F (apparent clearance of the analyte in the plasma after extravascular administration)	up to 168 hours after administration
Vz/F (apparent volume of distribution during the terminal phase λz of the analyte following an extravascular dose)	up to 168 hours after administration
Number of patients with adverse events	up to 11 weeks
Assessment of tolerability on a 4-point scale by investigator	14 days after last study drug administration
AUC0-24 h (area under the concentration-time curve of BI 1356 and metformin in plasma over the time interval from 0 to the 24 h)	up to 24 h after administration
AUC0-tz (area under the concentration-time curve of BI 1356 and metformin in plasma over the time interval from 0 to the time of the last quantifiable data point)	up to 168 h after administration
AUC0-∞ (area under the concentration time curve of BI 1356 in plasma over the time interval from 0 extrapolated to infinity)	up to 168 h after administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): June 1, 2009
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: June 24, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 25, 2014

Study Record Updates

• Last Update Posted (Estimate): July 8, 2014
• Last Update Submitted That Met QC Criteria: July 4, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Linagliptin
• Other Study ID Numbers: 1218.47

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No