Pharmacokinetics and Pharmacodynamics of Multiple 5 mg Doses of BI 1356 p.o. Given Once Daily Compared to Multiple 2.5 mg Doses Given Twice Daily in Healthy Male and Female Volunteers

Study Overview
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Brief Summary
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The objective was to investigate the influence of 2 different dosage regimens (5 mg once daily vs. 2.5 mg twice daily) on the steady-state pharmacokinetics and pharmacodynamics of orally administered BI 1356.

Official Title
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Pharmacokinetics and Pharmacodynamics of Multiple 5 mg Doses of BI 1356 p.o. Given Once Daily Compared to Multiple 2.5 mg Doses Given Twice Daily in Healthy Male and Female Volunteers. A Monocentric, Open Label, Cross-over Trial

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 1356, high dose
* Drug: BI 1356, low dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy females and males based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests Age ≥18 and Age ≤65 years BMI ≥18.5 and BMI ≤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 (including BP, PR and ECG) deviating from normal and of clinical relevance 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 (e.g. HIV) History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within two months prior to administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) 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 male subjects: Not willing to use adequate contraception (condome use plus another form of contraception e.g. spermicide, oral contraceptive taken by female partner, sterilisation, IUD (intrauterine device)) during the whole study period from the time of the first intake of study drug until one month after the last intake For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test Are not willing or are unable to use a reliable method of contraception (such as implants, injectibles and combined oral contraceptives, sterilisation, IUD, double barrier method) for at least 3 months prior to participation in the trial, during and up to 2 months after completion/termination of the trial Chronic use of oral contraception or hormone replacement containing ethinyl estradiol as the only method of contraception Lactation period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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, high dose<br>Treatment A: 7 days of BI 1356 treatment given once daily | Drug: BI 1356, high dose<br> <br> |
| Active Comparator: BI 1356, low dose<br>Treatment B: 7 days of BI 1356 treatment given twice daily | Drug: BI 1356, low dose<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-24,ss (area under the concentration-time curve of the analyte in plasma over the time interval 0 to 24 hours at steady state) |  | up to 336 h after first administration of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax,ss (concentration of the analyte in plasma at steady state after administration of the last dose at the end of the dosing interval) |  | up to 336 h after first administration of study drug | 
| Cpre,N (predose concentration of the analyte in plasma immediately before administration of the Nth dose after N-1 doses were administered) |  | up to 336 h after first administration of study drug | 
| tmax,ss (time from last dosing to maximum concentration of the analyte in plasma at steady state over a uniform dosing interval τ) |  | up to 336 h after first administration of study drug | 
| AUCss (area under the concentration-time curve of the analyte in plasma at steady state) for several time points |  | up to 336 h after first administration of study drug | 
| MRTpo,ss (mean residence time of the analyte in the body at steady state after oral administration) |  | up to 336 h after first administration of study drug | 
| CL/F,ss (apparent clearance of the analyte in the plasma after extravascular administration at steady state) |  | up to 336 h after first administration of study drug | 
| CLR,ss (renal clearance of the analyte at steady state determined over the dosing interval τ) |  | up to 336 h after first administration of study drug | 
| Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following extravascular administration) |  | up to 336 h after first administration of study drug | 
| Aet1-t2 (amount of BI 1356 excreted in the urine over the time interval t1 to t2 at steady-state) |  | 0-12h and 12-24h after drug administration on day 7 and day 14 | 
| fet1-t2 (fraction of BI 1356 excreted in urine over the time interval form t1 to t2) |  | 0-12h and 12-24h after drug administration on day 7 and day 14 | 
| Number of patients with clinically relevant findings in vital signs (blood pressure (BP), pulse rate (PR)) |  | Baseline, up to 26 days | 
| Number of patients with clinically relevant findings in 12-lead ECG (electrocardiogram) |  | Baseline, up to 26 days | 
| Number of patients with clinically relevant findings in clinical laboratory tests |  | Baseline, up to 26 days | 
| Incidence of adverse events (AEs) |  | up to 47 days | 
| Assessment of tolerability on a 4-point scale by investigator |  | Day 7, 15 and 26 | 
| Dipeptidyl peptidase-4 (DPP-4) inhibition at steady state |  | up to 336 h after first administration of study drug |