Effect of Cytochrome P 450 3A4 Inhibition by Itraconazole on the Single Oral Dose Pharmacokinetics of Cilobradine

Study Overview
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Brief Summary
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Study to investigate the effect of cytochrome P 450 3A4 inhibition by itraconazole on the single dose pharmacokinetics of cilobradine

Official Title
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The Effect of Cytochrome P 450 3A4 Inhibition by Itraconazole on the Single Oral Dose Pharmacokinetics of Cilobradine (an Open-label, Randomised, Single-dose, Two-way Crossover Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Cilobradine, low dose
* Drug: Cilobradine, high dose
* Drug: Itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy 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 1.1 No finding deviating from normal and of clinical relevance 1.2 No evidence of a clinically relevant concomitant disease Age ≥21 and Age ≤55 years BMI ≥18.5 and BMI < 30 kg/m2 (Body Mass Index) Resting pulse rate (PR; after 10 min. in the supine position) of more than 55 bpm Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation Exclusion Criteria: Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, ophthalmological, or hormonal disorders 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 allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator 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 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 (more than 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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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: Cilobradine, low dose plus itraconazole<br>Pre-study | Drug: Cilobradine, low dose<br> <br> Drug: Itraconazole<br> <br> * Other names: Sempera®;|
| Active Comparator: Cilobradine, low dose<br>Pre-study | Drug: Cilobradine, low dose<br> <br> |
| Experimental: Cilobradine, high dose plus itraconazole<br>main study | Drug: Cilobradine, high dose<br> <br> Drug: Itraconazole<br> <br> * Other names: Sempera®;|
| Active Comparator: Cilobradine, high dose<br>main study | Drug: Cilobradine, high dose<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) |  | up to 56 hours after administration of Cilobradine | 
| Maximum measured concentration of the analyte in plasma (Cmax) |  | up to 56 hours after administration of Cilobradine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz) |  | up to 56 hours after administration of Cilobradine | 
| Time from dosing to Cmax (Tmax) |  | up to 56 hours after administration of Cilobradine | 
| Terminal rate constant in plasma (λz) |  | up to 56 hours after administration of Cilobradine | 
| Terminal half-life of the analyte in plasma (t1/2) |  | up to 56 hours after administration of Cilobradine | 
| Mean residence time of the analyte in the body after p.o. administration (MRTpo) |  | up to 56 hours after administration of Cilobradine | 
| Apparent clearance of the analyte in the plasma after extravascular administration (CL/F) |  | up to 56 hours after administration of Cilobradine | 
| Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F) |  | up to 56 hours after administration of Cilobradine | 
| Amount of parent compound excreted in urine with zero to 72 h in % of dose (fe0-tz) |  | up to 72 hours after administration of Cilobradine | 
| Renal clearance of cilobradine (CLR,0-tz) |  | up to 72 hours after administration of Cilobradine | 
| Number of subjects with adverse events |  | up to 46 days | 
| Occurrence of visual phenomena | questionnaire | up to 46 days | 
| Number of subjects with clinically relevant findings in vital signs | blood pressure, pulse rate | up to 32 days | 
| Number of subjects with clinically relevant findings in laboratory tests |  | up to 32 days | 
| Number of subjects with clinically relevant findings in 12-lead electrocardiogram |  | up to 32 days | 
| Assessment of tolerability by investigator on a 4-point scale |  | within 8 days after last PK sampling |