Pharmacokinetics, Safety and Tolerability of Digoxin With or Without Co-administration of BI 1356 in Healthy Volunteers

Relative Bioavailability of Digoxin After Co-administration of Multiple Oral Doses of Digoxin (0.25 mg qd) and Multiple Oral Doses of BI 1356 (5 mg qd) Compared to the Bioavailability of Multiple Oral Doses of Digoxin (0.25 mg qd) Alone in Healthy Male and Female Volunteers (an Open-label, Randomized, Two-way Crossover Clinical Phase I Study)

The purpose of this study is to investigate the pharmacokinetics, safety and tolerability of digoxin with and without co-administration of BI 1356. Additionally the steady state pharmacokinetics of BI 1356 when co-administered with digoxin will be determined.

Inclusion Criteria:

• Healthy females and males according to the following criteria: based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests
• Age ≥ 18 and age ≤ 50 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 GCP 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 five half-lives of the respective drug prior to administration or during the trial
• Use of drugs which could reasonably influence the results of the trial or that prolonged 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) or inability to stop alcoholic beverages for 24 hours prior to dosing and up to the last sampling time point
• 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 was 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 corrected QT 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:

• Pregnancy/positive pregnancy test, or planning to become pregnant during the study or within one month of study completion
• No adequate contraception during the study and until one month of study completion
• Lactation period

Exclusion criteria specific for this study:

• Bradycardia (< 50/min) or atrioventricular block (including I grade auriculoventricular (AV) block) at screening
• Creatinine clearance (Cockroft-Gault-Formula) < 80 mL/min at screening
• History of or actual thyroid dysfunction/disease, or basal thyroid-stimulating hormone (TSH) , free triiodothyronine (FT3), or free thyroxine (FT4) out of normal range at screening
• Any degree of hypokalemia, hypomagnesemia, or hypercalcemia at screening