Study to Evaluate the Effect of Multiple Doses of BIRT 2584 XX Tablets on the Pharmacokinetic Parameters of Warfarin, Omeprazole, Caffeine, and Dextromethorphan in Healthy Male Volunteers

Study Overview
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Brief Summary
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The study aimed to investigate the effect of BIRT 2584 XX and its metabolite BI 610100 on the Pharmacokinetics (PK) of five probe substrates for cytochrome P450 isozymes. The substrates used to monitor enzyme activity were oral warfarin (for CYP2C9), oral omeprazole (for CYP2C19), oral dextromethorphan (for CYP2D6), oral caffeine (for CYP1A2) and intravenous midazolam (for hepatic CYP3A)

Official Title
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A Study to Evaluate the Effect of Multiple Doses of 500 mg of BIRT 2584 XX Tablets on the Pharmacokinetic Parameters of Warfarin, Omeprazole, Caffeine, and Dextromethorphan Dosed Orally and Midazolam Dosed IV, in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: BIRT 2584 XX
* Drug: Warfarin sodium
* Drug: Omeprazole
* Drug: Dextromethorphan hydrobromide
* Drug: Caffeine
* Drug: Midazolam hydrochloride
* Drug: Vitamin K1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age ≥ 18 and ≤55 years BMI ≥ 18.5 and ≤ 29.9 kg/m2 healthy male subjects as determined by the investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs, and 12-lead ECG at the screening visit signed written informed consent in accordance with Good Clinical Practice (GCP) and local legislation non-smoker (a subject is considered to be a non-smoker if he has never smoked or has stopped smoking ≥ 6 months before the screening visit) agree not to take any prescription medications or non-prescription drugs (including herbal preparations and vitamins) without approval by the investigator and not to receive vaccinations during the course of the study agree not to eat oranges, grapefruits, broccoli, Brussels sprouts, or char grilled meats and not to drink grapefruit juice during the course of the study agree not to drink alcoholic beverages during the course of the study agree not to drink or eat caffeine and theobromine containing beverages and foods during the course of the study Exclusion Criteria: any finding of the medical examination (including Blood Pressure, Pulse Rate, and ECG) deviating from normal and of clinical relevance gastrointestinal, hepatic, renal, respiratory (e.g. asthma), cardiovascular, metabolic, immunologic, haematological, oncological, or hormonal disorders any surgical or medical condition that could interfere with the administration of the study drug or interpretation of the study results diseases of the Central nervous system (CNS) (such as epilepsy) or psychiatric disorders or neurological disorders relevant history of orthostatic hypotension, fainting spells, or blackouts chronic or relevant acute infections history of allergy/hypersensitivity (including drug allergy) considered relevant to the trial as judged by the investigator immunisation during the 2 weeks prior to the screening visit known intolerance to benzodiazepines known intolerance to the active and/or inactive ingredients in caffeine, warfarin, vitamin K1, omeprazole, or dextromethorphan known acute angle-closure glaucoma elevated prothrombin time as determined by Prothrombin time (INR) > 1.3 intake of drugs with a long half-life (greater than 24 hrs) (less than one month prior to administration or during the trial) use of any drugs which might influence the results of the trial (less than 10 days prior to study drug administration or expected during the trial) use of chewing tobacco or nicotine replacement devices within 6 months before the screening visit participation in another trial with an investigational drug within 2 months prior to administration or during the trial alcohol abuse (more than 60 g of ethanol per day) blood donation or loss greater than 100 mL (less than one month prior to administration or expected during the trial) clinically relevant laboratory abnormalities

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIRT 2584 XX + PK-cocktail<br> | Drug: BIRT 2584 XX<br> <br> Drug: Warfarin sodium<br> <br> * Other names: Coumadin®;Drug: Omeprazole<br> <br> * Other names: Omeprazole-ratiopharm® NT;Drug: Dextromethorphan hydrobromide<br> <br> * Other names: Hustenstiller-ratiopharm®;Drug: Caffeine<br> <br> * Other names: Coffeinum®;Drug: Midazolam hydrochloride<br> <br> * Other names: Dormicum®;Drug: Vitamin K1<br> <br> * Other names: Konakion®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-inf (Area under the concentration-time curve of midazolam IV and S-warfarin in plasma over the time interval from 0 extrapolated to infinity) |  | up to day 19 | 
| AUC (Area under the concentration-time curve of the ratio of omeprazole to 5-hydroxyomeprazole in plasma) |  | up to day 19 | 
| 0-12 hr urinary molar ratio of caffeine metabolites (1-Methylxanthine + 1-Methylurate +5-Acetylamino-6-formylamino-3-methyluracil)/ 1,7-Dimethylurate |  | up to 12 hours after administration | 
| 0-12 hr urinary dextromethorphan/dextrorphan ratio |  | up to 12 hours after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-tz (Area under the concentration-time curve of the S-warfarin, omeprazole and midazolam IV in plasma over the time interval from 0 to the time of the last quantifiable data point) |  | up to day 19 | 
| Cmax (Maximum measured concentration of the S-warfarin, omeprazole and midazolam IV in plasma) |  | up to day 19 | 
| tmax (Time from dosing to the maximum concentration of the S-warfarin, omeprazole and midazolam IV in plasma) |  | up to day 19 | 
| λz (Terminal rate constant of the S-warfarin, omeprazole and midazolam IV in plasma) |  | up to day 19 | 
| t1/2 (Terminal rate constant of the S-warfarin, omeprazole and midazolam IV in plasma) |  | up to day 19 | 
| MRT (Mean residence time of the S-warfarin, omeprazole and midazolam IV in the body after administration) |  | up to day 19 | 
| CL/F (Apparent clearance of the S-warfarin, omeprazole and midazolam IV in plasma after extravascular single dose administration) |  | up to day 19 | 
| Vz/F (Apparent volume of distribution during the terminal phase λz following extravascular administration S-warfarin, omeprazole and midazolam IV) |  | up to day 19 | 
| AUC0-inf (Area under the concentration-time curve of omeprazole in plasma over the time interval from 0 extrapolated to infinity) |  | up to day 19 | 
| trough levels of BIRT 2584 XX and BI 610100 |  | up to day 19 | 
| approximate peak levels of BIRT 2584 XX and BI 610100 |  | up to day 19 | 
| Number of subjects with adverse events |  | up to 48 days | 
| Number of subjects with abnormal changes in laboratory parameters |  | up to 48 days |