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

Study Overview
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Brief Summary
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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.

Official Title
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Evaluating the Effects of Tipranavir (With Ritonavir) Capsule and Liquid Formulation on Cytochrome P450 and P-glycoprotein Activity Using a Biomarker Cocktail in Healthy Human Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Tipranavir capsule
* Drug: Tipranavir solution
* Drug: Ritonavir capsule
* Drug: Caffeine
* Drug: Warfarin sodium
* Drug: Vitamin K
* Drug: Omeprazole
* Drug: Dextromethorphan hydrobromide
* Drug: Midazolam injection
* Drug: Midazolam oral solution
* Drug: Digoxin tablet
* Drug: Digoxin injection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral | Drug: Tipranavir capsule<br> <br> Drug: Ritonavir capsule<br> <br> Drug: Caffeine<br> <br> Drug: Warfarin sodium<br> <br> Drug: Vitamin K<br> <br> Drug: Omeprazole<br> <br> Drug: Dextromethorphan hydrobromide<br> <br> Drug: Midazolam injection<br> <br> Drug: Midazolam oral solution<br> <br> Drug: Digoxin tablet<br> <br> |
| Experimental: Treatment B<br>TPV capsule + RTV capsule + cocktail + digoxin injection | Drug: Tipranavir capsule<br> <br> Drug: Ritonavir capsule<br> <br> Drug: Caffeine<br> <br> Drug: Warfarin sodium<br> <br> Drug: Vitamin K<br> <br> Drug: Omeprazole<br> <br> Drug: Dextromethorphan hydrobromide<br> <br> Drug: Midazolam injection<br> <br> Drug: Midazolam oral solution<br> <br> Drug: Digoxin injection<br> <br> |
| Experimental: Treatment C<br>TPV solution + RTV capsule + cocktail + digoxin oral | Drug: Tipranavir solution<br> <br> Drug: Ritonavir capsule<br> <br> Drug: Caffeine<br> <br> Drug: Warfarin sodium<br> <br> Drug: Vitamin K<br> <br> Drug: Omeprazole<br> <br> Drug: Dextromethorphan hydrobromide<br> <br> Drug: Midazolam injection<br> <br> Drug: Midazolam oral solution<br> <br> Drug: Digoxin tablet<br> <br> |
| Experimental: Treatment D<br>TPV solution + RTV capsule + cocktail + digoxin injection | Drug: Tipranavir solution<br> <br> Drug: Ritonavir capsule<br> <br> Drug: Caffeine<br> <br> Drug: Warfarin sodium<br> <br> Drug: Vitamin K<br> <br> Drug: Omeprazole<br> <br> Drug: Dextromethorphan hydrobromide<br> <br> Drug: Midazolam injection<br> <br> Drug: Midazolam oral solution<br> <br> Drug: Digoxin injection<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration-time curve (AUC) at steady state |  | up to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Apparent terminal half-life (t1/2) |  | up to 72 hours | 
| Area under plasma concentration-time curve (AUC) after single dose |  | up to 72 hours | 
| Change in biomarkers |  | baseline, up to 22 days | 
| Change in enzyme activity |  | baseline, up to 22 days |