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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Omeprazole; Drug: Caffeine; Drug: Midazolam injection; Drug: Warfarin sodium; Drug: Dextromethorphan hydrobromide; Drug: Tipranavir capsule; Drug: Ritonavir capsule; Drug: Vitamin K; Drug: Midazolam oral solution; Drug: Digoxin tablet; Drug: Digoxin injection; Drug: Tipranavir solution

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed informed consent
2. Healthy subjects aged between 18 years and 45 years inclusive
3. Weighing at least 50 kg
4. 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)
5. Volunteers must be willing to complete all study-related activities
6. Each volunteer must have a valid social security number
7. Each volunteer must have acceptable medical history, physical examination and laboratory test

Exclusion Criteria:

1. 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
2. Any finding of the medical examination (including blood pressure, pulse rate and electrocardiogram) deviating from normal and of clinical relevance
3. 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
4. Known elevated liver enzymes in past clinical trials with any compound (experimental or marketed)
5. 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)
6. History of evidence of clinically significant hepatic, cardiac, pulmonary, endocrine, immunological, gastrointestinal, hematological, vascular or collagen disease
7. History of alcohol abuse or use of any illicit drugs
8. Unable to abstain from more than one beer or alcohol equivalent per day for the duration of the study
9. Use of tobacco products and/or history of smoking within the past 2 months
10. Pregnant or breast feeding
11. Sexually active women of childbearing age who do not use an acceptable barrier method of birth control
12. Hypersensitivity to caffeine, warfarin, vitamin K, omeprazole, dextromethorphan, midazolam, tipranavir, ritonavir or their excipients
13. Concomitant treatment with other experimental compounds
14. Concomitant administration of any prescription or over the counter medications known to alter P450 enzyme or P-gp activity
15. 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
16. Concomitant administration of any food product known to alter P450 enzyme or P-gp activity such as grapefruit juice, Seville oranges
17. Concomitant administration of any drug that could affect bleeding (e.g., aspirin, clopidogrel, ticlopidine, warfarin, heparin, low-molecular weight heparin)
18. Concomitant administration of oral contraceptives (may be included with 7-day washout period)
19. Concomitant administration of any herbal medications
20. Inadequate venous access
21. Renal or hepatic insufficiency
22. Clinically unacceptable result at the screening physical examination
23. Use of investigational medications within 30 days before study entry
24. HIV-positive
25. Body Mass Index (BMI) > 30 kg/m²

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum plasma concentration (Cmax)	up to 12 hours
Plasma concentration after 12 hours (Cp12h)	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): July 1, 2006

Study Registration Dates

• First Submitted: September 1, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimate): September 18, 2014

Study Record Updates

• Last Update Posted (Estimate): September 18, 2014
• Last Update Submitted That Met QC Criteria: September 16, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Central Nervous System Depressants; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Respiratory System Agents; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Digoxin; Midazolam; Vitamin K; Ritonavir; Pharmaceutical Solutions; Dextromethorphan; Tipranavir; Warfarin; Caffeine; Omeprazole
• Other Study ID Numbers: 1182.101