Effects of BI 201335 NA on Cytochrome P450 and P-glycoprotein Activity Using a Probe Drug Cocktail in Healthy Volunteers

Study Overview
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Brief Summary
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The objective of this trial was to quantify the effect of oral single-dose (480 mg) and steady-state BI 201335 NA (240 mg BID) on intestinal and hepatic cytochrome P450 (CYP) and P-glycoprotein (P-gp) probe drugs as a means of predicting drug interactions. The AUCs for the probe drugs caffeine, warfarin, omeprazole, dextromethorphan, midazolam, and digoxin were assessed.

Official Title
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Evaluation of the Effects of Single Oral Dose and Multiple Oral Doses of BI 201335 NA on Cytochrome P450 and P-glycoprotein Activity Using a Probe Drug Cocktail. An Open-label, Single-arm Phase I Study in Healthy Human Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 201335 NA
* Drug: Caffeine
* Drug: Warfarin sodium
* Drug: Vitamin K
* Drug: Omeprazole
* Drug: Dextromethorphan hydrobromide
* Drug: Midazolam HCl solution
* Drug: Midazolam HCl oral syrup
* Drug: Digoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent prior to admission to the study in accordance with GCP (Good Clinical Practice) and the local legislation Healthy males and female subjects age ≥18 to ≤55 years and according to the following criteria: Complete medical history, including the physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead EKG (electrocardiogram)(including determination of QTcB, and QtcF intervals), and clinical laboratory tests; all with acceptable findings Weighing at least 50 kg, and BMI ≥18.5 and BMI ≤29.9 kg/m2 (Body Mass Index) Volunteers must not leave the research unit, during the days of over-night stays, which include the periods from evening of Day-1 to morning of Day 5, and evening of Day 9 to morning of Day 24 Volunteers must be willing to complete all study-related activities Exclusion Criteria: Any finding of the medical examination (including blood pressure, pulse rate and EKG) deviating from normal and of clinical relevance, as assessed by the investigator Active diseases of the gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, musculoskeletal, immunologic, rheumatologic, hormonal, neurological system, cancer, or bleeding disorders that require current medical treatment, may be unstable, or may be exacerbated by participation in the study Any evidence of a clinically relevant concomitant disease, which is not defined in the exclusion criteria 2 above, including but not limited to relevant chronic or acute infection Surgery of the gastrointestinal tract (except appendectomy and endoscopic removal of colon polyps) History or presence of allergy to any of the study drugs (e.g., BI 201335 NA, caffeine, warfarin, vitamin K, omeprazole, dextromethorphan, digoxin, midazolam, omeprazole) or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation Concomitant drugs, nutraceuticals, and herbal remedies that in the opinion of the investigator (in consultation with the BI medical monitor or pharmacokineticist), would interfere with either the absorption, distribution or metabolism of BI 201335 NA, or other study drugs Use of drugs, which might reasonably influence the results of the trial or that prolong the QT/QTc interval within 30 days prior to screening until trial completion Use of any investigational drug within 30 days prior to enrollment; or the planned usage of any investigational drug during the course of the current study Smoking (>10 cigarettes or >3 cigars or >3 pipes/day) Inability to abstain from alcohol from day of screening to 7 days after last study drug administration. 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 at screening, according to the judgment of the investigator, and in consultation with the clinical monitor Known elevated liver enzymes in past with any compound (experimental or marketed) Concomitant administration of any food product known to alter P450 enzyme or P-gp activity such as grapefruit juice, Seville oranges, St. John's Wort Concomitant administration of any drug that could affect bleeding (e.g., aspirin, clopidogrel, ticlopidine, warfarin in addition to the studied warfarin dose, heparin, low-molecular weight heparin) Concomitant administration of oral contraceptives (may be included with 7-day washout period) Inadequate venous access Renal or hepatic insufficiency A marked baseline prolongation of QT/QTc interval e.g., repeated demonstration of a QTcF, or QTcB interval >450 ms) Infection with hepatitis B (HBV), or hepatitis C virus (HCV), defined as either being hepatitis B surface antigen and /or hepatitis B core antibody positive, or hepatitis C antibody positive) Positive Enzyme-linked immunosorbent assay (ELISA) for Human Immunodeficiency Virus (HIV)-1 or HIV-2 Fasting screening laboratory testing with direct bilirubin within the normal range and elevated total bilirubin, defined as 30% above the upper limit of normal For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test at screening visit No adequate contraception, e.g., sterilisation, IUD (intrauterine device), have not been using a barrier method of contraception for at least 3 months prior to participation in the study Are not willing or are unable to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during and up to 2 months after completion/termination of the trial Lactation period with active breastfeeding from time of screening to 30 days after end of trial visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 201335 NA<br> | Drug: BI 201335 NA<br>* 480 mg BI 201335 NA in the morning, 240 mg BI 201335 NA in the evening of day 10 240 mg BI 201335 NA bid from day 11 to 23<br>Drug: Caffeine<br>* days 1, 10 and 19<br>Drug: Warfarin sodium<br>* days 1, 10 and 19<br>Drug: Vitamin K<br>* days 1, 10 and 19<br>Drug: Omeprazole<br>* days 1, 10 and 19<br>Drug: Dextromethorphan hydrobromide<br>* days 1, 10 and 19<br>Drug: Midazolam HCl solution<br>* Days 3 and 21<br>Drug: Midazolam HCl oral syrup<br>* days 1, 10 and 19<br>Drug: Digoxin<br>* Days 2 and 20<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) 0-24h of caffeine |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 hours after treatment on days 1, 10 and 19 | 
| AUC0-120h of Warfarin |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours after treatment on days 1, 10 and 19 | 
| AUC0-24h of Omeprazole |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 hours after treatment on days 1, 10 and 19 | 
| AUC0-24h of Dextromethorphan |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 hours after treatment on days 1, 10 and 19 | 
| AUC0-24h of Midazolam IV |  | Pre-dose and 0.08, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours after treatment on days 3 and 21 | 
| AUC0-24h of Midazolam oral |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 hours after treatment on days 1, 10 and 19 | 
| AUC0-96h of Digoxin |  | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours after treatment on days 2 and 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of caffeine |  | Baseline and day 1, day 1 and day 19 | 
| Cmax (Maximum Plasma Concentration after a single dose) of caffeine |  | Baseline and day 1, baseline and day 19 | 
| Ct (Plasma concentration at a given time t after a single dose) of caffeine |  | Baseline and day 1, baseline and day 19 | 
| tmax (Time of Maximum Concentration after a single dose) of caffeine |  | Baseline and day 1, baseline and day 19 | 
| CL/F (Oral Clearance after a single dose) of caffeine |  | Baseline and day1, baseline and day 19 | 
| t1/2 (Apparent Terminal Half-Life) of caffeine |  | Baseline and day 1, baseline and day 19 | 
| AUC of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| Cmax of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| Ct of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| tmax of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| CL/F of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| t1/2 of Warfarin |  | Baseline and day 1, day 1 and day 19 | 
| AUC of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| Cmax of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| Ct of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| tmax of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| CL/F of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| t1/2 of Omeprazole |  | Baseline and day 1, day 1 and day 19 | 
| AUC of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| Cmax of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| Ct of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| tmax of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| CL/F of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| t1/2 of Dextromethorphan |  | Baseline and day 1, day 1 and day 19 | 
| AUC of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| Cmax of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| Ct of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| tmax of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| CL/F of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| t1/2 of Midazolam IV |  | Baseline and day 1, day 1 and day 19 | 
| AUC of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| Cmax of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| Ct of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| tmax of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| CL/F of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| t1/2 of Midazolam oral |  | Baseline and day 1, baseline and day 19 | 
| AUC of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| Cmax of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| Ct of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| tmax of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| CL/F of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| t1/2 of Digoxin |  | Baseline and day 1, baseline and day 19 | 
| AUCτ,N (Uniform Dosing Interval τ Following the Nth Dose) of BI201335 NA |  | Day 10 | 
| AUCτ,ss,N of BI201335 NA |  | Day 19 | 
| Cmax,N of BI 201335 NA |  | Day 10 | 
| Cmax,ss,N of BI 201335 NA |  | Day 19 | 
| tmax,N of BI 201335 NA |  | Day 10 | 
| tmax,ss,N of BI 201335 NA |  | Day 19 | 
| Cmin,N of BI 201335 NA |  | Day 10 | 
| Cmin,ss,N of BI 201335 NA |  | Day 19 | 
| CL/F,ss,N of BI 201335 NA |  | Day 19 | 
| Urinary metabolic ratios of the analyte of first-day and steady state |  | up to day 19 |