Effects of Tipranavir (With Ritonavir) Capsule and Liquid Formulation on Cytochrome P450 and P-glycoprotein Activity in Healthy Volunteers

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