Effect of Multiple BI 1356 Doses of on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Healthy Female Premenopausal Subjects

An Open, Two-period, Fixed-sequence, Phase I Trial to Evaluate the Effect of Multiple Doses of BI 1356 on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel

The objective was to investigate the effect of multiple oral doses of 5 mg BI 1356 on the steady-state pharmacokinetics of ethinylestradiol (EE) and levonorgestrel (LNG), the components of Microgynon®

Inclusion Criteria:

• Healthy premenopausal female subjects as determined by the results of screening based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), heart rate (HR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
• Age 18 - 40 years
• BMI 18.5 - 27 kg/m2 (Body Mass Index)
• Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation
• Gynaecological examination without relevant findings

Exclusion Criteria:

• Any finding of the medical examination deviating from normal and of clinical relevance. Systolic blood pressure greater than 140 mm Hg or 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 or hypersensitivity (including allergy to drug or its excipients)
• Intake of drugs with a long half-life (greater than 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to day 1 or during the trial
• Use of antibiotics and drugs known to inhibit or induce cytochrome P450 enzymes, especially CYP3A4, within one month prior to study day 1 or during the trial (CYP3A4 inhibitors are for example azole antimycotics, macrolides, CYP3A inducers are for example St. John's Wort or certain anticonvulsants)
• Participation in another trial with an investigational drug within two months prior to day 1 or during the trial
• Regular smokers of more than two cigarettes daily
• Drug or alcohol abuse (more than 20 g alcohol/day)
• Blood donation (more than 100 mL within four weeks prior to day 1)
• Excessive physical activities within 48 hours prior to day 1)
• Any laboratory value outside the reference range that is of clinical relevance
• Inability to comply with dietary regimen of trial site
• Positive pregnancy test, pregnancy or planning to become pregnant within 2 months of study completion, or lactation
• No use of an additional contraceptive method until 6 weeks after last study drug administration, i.e. barrier method, sexual abstinence, non-hormone-containing intrauterine device (IUD), surgical sterilisation (incl. hysterectomy) or vasectomized partner
• Use of oral contraceptive-containing intrauterine device, depot injection or contraceptive implants
• Existing or a history of confirmed venous thromboembolism (VTE), family history of idiopathic VTE and other known risk factors for VTE. Existing or previous arterial thrombotic or embolic processes, conditions which predispose to them e.g. disorders of the clotting processes, valvular heart disease and atrial fibrillation
• Relevant varicosis
• History of migraine
• History of liver disease, i.e. disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours
• Clinically relevant cycle anomalies and dysmenorrhoea within the last 12 months
• Usual menstrual cycle duration outside of a 26-32 days range