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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 1356/metformin
* Drug: BI 1356
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1356/metformin<br> | Drug: BI 1356/metformin<br>* fixed dose combination tablet<br>|
| Experimental: BI 1356 + Metformin<br> | Drug: BI 1356<br> <br> Drug: Metformin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |