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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Cilobradine, low dose; Drug: Cilobradine, high dose; Drug: Itraconazole

• Registration Number: NCT02264041
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study Start: 2004-01
• Primary Completion: 2004-04
• Status Verified: 2014-10
• Study First Submitted: 2014-10-13
• Study First Submitted QC: 2014-10-13
• Last Update Submitted: 2014-10-13
• Study First Posted: 2014-10-15
• Last Update Posted: 2014-10-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 25

Inclusion Criteria

1. 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

2. Age ≥21 and Age ≤55 years

3. BMI ≥18.5 and BMI < 30 kg/m2 (Body Mass Index)

4. Resting pulse rate (PR; after 10 min. in the supine position) of more than 55 bpm

5. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation

Exclusion Criteria

1. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, ophthalmological, or hormonal disorders
2. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
3. History of relevant orthostatic hypotension, fainting spells or blackouts.
4. Chronic or relevant acute infections
5. History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator
6. 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
7. 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.
8. Participation in another trial with an investigational drug within two months prior to administration or during the trial
9. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes/day)
10. Inability to refrain from smoking on trial days
11. Alcohol abuse (more than 60 g/day)
12. Drug abuse
13. Blood donation (more than 100 mL within four weeks prior to administration or during the trial)
14. Excessive physical activities (within one week prior to administration or during the trial)
15. Any laboratory value outside the reference range that is of clinical relevance

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Cilobradine, low dose plus itraconazole	Itraconazole	Pre-study
Cilobradine, low dose plus itraconazole	Cilobradine, low dose	Pre-study
Cilobradine, low dose	Cilobradine, low dose	Pre-study
Cilobradine, high dose plus itraconazole	Cilobradine, high dose	main study
Cilobradine, high dose plus itraconazole	Itraconazole	main study
Cilobradine, high dose	Cilobradine, high dose	main study

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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
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
Number of subjects with clinically relevant findings in vital signs	up to 32 days	blood pressure, pulse rate
Occurrence of visual phenomena	up to 46 days	questionnaire
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
Terminal half-life of the analyte in plasma (t1/2)	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
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
Number of subjects with adverse events	up to 46 days