Healthy
Conditions
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.
Interventions
DRUGTipranavir capsule
DRUGTipranavir solution
DRUGRitonavir capsule
DRUGCaffeine
DRUGWarfarin sodium
DRUGVitamin K
DRUGOmeprazole
DRUGMidazolam injection
DRUGDigoxin tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area under plasma concentration-time curve (AUC) at steady state | up to 72 hours |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Plasma concentration after 12 hours (Cp12h) | 12 hours |
| Change in biomarkers | baseline, up to 22 days |
| Change in enzyme activity | baseline, up to 22 days |
| Area under plasma concentration-time curve (AUC) after single dose | up to 72 hours |
Outcome results
None listed