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

NCT02182336 | Completed Phase 1

• 1 other identifier: 1220.32
• Study Type: interventional
• Target: 23
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Healthy

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (52)

• 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

Study Arms (1)

BI 201335 NA

EXPERIMENTAL

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

Interventions

BI 201335 NA DRUG

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

BI 201335 NA

Caffeine DRUG

days 1, 10 and 19

BI 201335 NA

Warfarin sodium DRUG

days 1, 10 and 19

BI 201335 NA

Vitamin K DRUG

days 1, 10 and 19

BI 201335 NA

Omeprazole DRUG

days 1, 10 and 19

BI 201335 NA

Dextromethorphan hydrobromide DRUG

days 1, 10 and 19

BI 201335 NA

Midazolam HCl solution DRUG

Days 3 and 21

BI 201335 NA

Midazolam HCl oral syrup DRUG

days 1, 10 and 19

BI 201335 NA

Digoxin DRUG

Days 2 and 20

BI 201335 NA

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Boehringer Ingelheim: lead

MeSH Terms

Interventions

Caffeine; Warfarin; Vitamin K; Omeprazole; Dextromethorphan; Digoxin

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Phytol; Diterpenes; Terpenes; Polycyclic Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Benzimidazoles; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Glycosides; Carbohydrates

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2014
• First Posted: July 8, 2014
• Study Start: June 1, 2008
• Primary Completion: September 1, 2008
• Last Updated: July 18, 2014

Record last verified: 2014-07