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

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

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)

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Omeprazole; Drug: Caffeine; Drug: BIRT 2584 XX; Drug: Warfarin sodium; Drug: Dextromethorphan hydrobromide; Drug: Midazolam hydrochloride; Drug: Vitamin K1

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): December 1, 2005

Study Registration Dates

• First Submitted: October 2, 2014
• First Submitted That Met QC Criteria: October 2, 2014
• First Posted (Estimate): October 6, 2014

Study Record Updates

• Last Update Posted (Estimate): October 6, 2014
• Last Update Submitted That Met QC Criteria: October 2, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Respiratory System Agents; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Midazolam; Vitamin K; Dextromethorphan; Warfarin; Caffeine; Omeprazole; Vitamin K 1
• Other Study ID Numbers: 1206.10