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

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)

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Itraconazole; Drug: Cilobradine, low dose; Drug: Cilobradine, high dose

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cilobradine, low dose plus itraconazole; Pre-study	Drug: Itraconazole; Other Names: Sempera®; Drug: Cilobradine, low dose
Active Comparator: Cilobradine, low dose; Pre-study	Drug: Cilobradine, low dose
Experimental: Cilobradine, high dose plus itraconazole; main study	Drug: Itraconazole; Other Names: Sempera®; Drug: Cilobradine, high dose
Active Comparator: Cilobradine, high dose; main study	Drug: Cilobradine, high dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2004
• Primary Completion (Actual): April 1, 2004

Study Registration Dates

• First Submitted: October 13, 2014
• First Submitted That Met QC Criteria: October 13, 2014
• First Posted (Estimate): October 15, 2014

Study Record Updates

• Last Update Posted (Estimate): October 15, 2014
• Last Update Submitted That Met QC Criteria: October 13, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole
• Other Study ID Numbers: 503.213