Healthy
Conditions
Brief summary
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.
Interventions
DRUGBI 201335 NA
1. 480 mg BI 201335 NA in the morning, 240 mg BI 201335 NA in the evening of day 10 2. 240 mg BI 201335 NA bid from day 11 to 23
DRUGCaffeine
days 1, 10 and 19
DRUGWarfarin sodium
days 1, 10 and 19
DRUGVitamin K
days 1, 10 and 19
DRUGOmeprazole
days 1, 10 and 19
days 1, 10 and 19
DRUGMidazolam HCl solution
Days 3 and 21
DRUGMidazolam HCl oral syrup
days 1, 10 and 19
DRUGDigoxin
Days 2 and 20
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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 |
| AUC of caffeine | Baseline and day 1, day 1 and day 19 |
| Urinary metabolic ratios of the analyte of first-day and steady state | up to 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 |
Outcome results
None listed