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: Drug: Tipranavir solution; Drug: Tipranavir capsule; 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

• 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

Study Timeline

• Study Start: 2006-01
• Primary Completion: 2006-07
• Status Verified: 2014-08
• Study First Submitted: 2014-09-01
• Study First Submitted QC: 2014-09-16
• Last Update Submitted: 2014-09-16
• Study First Posted: 2014-09-18
• Last Update Posted: 2014-09-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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 & 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
Maximum plasma concentration (Cmax)	up to 12 hours
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
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