Effects of Tipranavir (With Ritonavir) Capsule and Liquid Formulation on Cytochrome P450 and P-glycoprotein Activity in Healthy Volunteers
Phase 1
Completed
- Conditions
- Healthy
- Interventions
- Registration Number
- NCT02243553
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
Primary: To quantify the influence of single-dose and steady-state tipranavir/ritonavir 500/200 mg on intestinal and hepatic cytochrome P450 (CYP) and P-glycoprotein (P-gp) biomarkers, as a means of predicting drug interactions. The AUCs for biomarkers caffeine, warfarin, omeprazole, dextromethorphan, midazolam, and digoxin will be assessed.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 34
Inclusion Criteria
- Signed informed consent
- Healthy subjects aged between 18 years and 45 years inclusive
- Weighing at least 50 kg
- Volunteers must be hospitalized on Days 1-4, 7-9, and 17-20 for pharmacokinetic assessments for each biomarker and TPV/r (Days 7-9 and 17-20)
- Volunteers must be willing to complete all study-related activities
- Each volunteer must have a valid social security number
- Each volunteer must have acceptable medical history, physical examination and laboratory test
Exclusion Criteria
- History or presence of allergy to the study drugs 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
- Any finding of the medical examination (including blood pressure, pulse rate and electrocardiogram) deviating from normal and of clinical relevance
- History or diagnosis of any significant medical conditions: Including but not limited to gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic, hematological, psychiatric, neurological, oncological or hormonal disorders
- Known elevated liver enzymes in past clinical trials with any compound (experimental or marketed)
- Clinically relevant laboratory abnormalities (e.g. Hgb<11g/dL, Hct<30g/dL, total cholesterol >240mg/dL, triglycerides >500mg/dL, fasting glucose >130mg/dL, liver function tests >2.5x upper limit of normal, baseline international normalized ratio >1.2)
- History of evidence of clinically significant hepatic, cardiac, pulmonary, endocrine, immunological, gastrointestinal, hematological, vascular or collagen disease
- History of alcohol abuse or use of any illicit drugs
- Unable to abstain from more than one beer or alcohol equivalent per day for the duration of the study
- Use of tobacco products and/or history of smoking within the past 2 months
- Pregnant or breast feeding
- Sexually active women of childbearing age who do not use an acceptable barrier method of birth control
- Hypersensitivity to caffeine, warfarin, vitamin K, omeprazole, dextromethorphan, midazolam, tipranavir, ritonavir or their excipients
- Concomitant treatment with other experimental compounds
- Concomitant administration of any prescription or over the counter medications known to alter P450 enzyme or P-gp activity
- Concomitant administration of any prescription or over the counter medications known to be highly dependent on P450 or P-gp for clearance for which elevated plasma concentrations are known to be associated with serious toxicity
- Concomitant administration of any food product known to alter P450 enzyme or P-gp activity such as grapefruit juice, Seville oranges
- Concomitant administration of any drug that could affect bleeding (e.g., aspirin, clopidogrel, ticlopidine, warfarin, heparin, low-molecular weight heparin)
- Concomitant administration of oral contraceptives (may be included with 7-day washout period)
- Concomitant administration of any herbal medications
- Inadequate venous access
- Renal or hepatic insufficiency
- Clinically unacceptable result at the screening physical examination
- Use of investigational medications within 30 days before study entry
- HIV-positive
- Body Mass Index (BMI) > 30 kg/m²
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment B Midazolam oral solution TPV capsule + RTV capsule + cocktail + digoxin injection Treatment C Midazolam oral solution TPV solution + RTV capsule + cocktail + digoxin oral Treatment C Digoxin tablet TPV solution + RTV capsule + cocktail + digoxin oral Treatment D Tipranavir solution TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Caffeine TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Warfarin sodium TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Midazolam injection TPV solution + RTV capsule + cocktail + digoxin injection Treatment A Vitamin K tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment A Omeprazole tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment A Dextromethorphan hydrobromide tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment A Midazolam injection tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment B Vitamin K TPV capsule + RTV capsule + cocktail + digoxin injection Treatment C Omeprazole TPV solution + RTV capsule + cocktail + digoxin oral Treatment A Caffeine tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment B Midazolam injection TPV capsule + RTV capsule + cocktail + digoxin injection Treatment C Dextromethorphan hydrobromide TPV solution + RTV capsule + cocktail + digoxin oral Treatment A Ritonavir capsule tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment A Warfarin sodium tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment B Caffeine TPV capsule + RTV capsule + cocktail + digoxin injection Treatment A Midazolam oral solution tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment A Digoxin tablet tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment B Tipranavir capsule TPV capsule + RTV capsule + cocktail + digoxin injection Treatment B Ritonavir capsule TPV capsule + RTV capsule + cocktail + digoxin injection Treatment B Dextromethorphan hydrobromide TPV capsule + RTV capsule + cocktail + digoxin injection Treatment C Tipranavir solution TPV solution + RTV capsule + cocktail + digoxin oral Treatment C Ritonavir capsule TPV solution + RTV capsule + cocktail + digoxin oral Treatment A Tipranavir capsule tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral Treatment B Digoxin injection TPV capsule + RTV capsule + cocktail + digoxin injection Treatment D Midazolam oral solution TPV solution + RTV capsule + cocktail + digoxin injection Treatment C Midazolam injection TPV solution + RTV capsule + cocktail + digoxin oral Treatment D Vitamin K TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Digoxin injection TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Ritonavir capsule TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Omeprazole TPV solution + RTV capsule + cocktail + digoxin injection Treatment D Dextromethorphan hydrobromide TPV solution + RTV capsule + cocktail + digoxin injection Treatment B Warfarin sodium TPV capsule + RTV capsule + cocktail + digoxin injection Treatment B Omeprazole TPV capsule + RTV capsule + cocktail + digoxin injection Treatment C Vitamin K TPV solution + RTV capsule + cocktail + digoxin oral Treatment C Caffeine TPV solution + RTV capsule + cocktail + digoxin oral Treatment C Warfarin sodium TPV solution + RTV capsule + cocktail + digoxin oral
- Primary Outcome Measures
Name Time Method Area under plasma concentration-time curve (AUC) at steady state up to 72 hours
- Secondary Outcome Measures
Name Time Method Apparent terminal half-life (t1/2) up to 72 hours Change in biomarkers baseline, up to 22 days Plasma concentration after 12 hours (Cp12h) 12 hours Maximum plasma concentration (Cmax) up to 12 hours Time of maximum concentration (Tmax) up to 72 hours Area under plasma concentration-time curve (AUC) after single dose up to 72 hours Change in enzyme activity baseline, up to 22 days