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

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ClinicalTrials.gov Identifier: NCT02243553
Recruitment Status : Completed
First Posted : September 18, 2014
Last Update Posted : September 18, 2014
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Healthy 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 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : January 2006
Actual Primary Completion Date : July 2006

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment A
tipranavir (TPV) capsule + ritonavir (RTV) capsule + cocktail + digoxin oral
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
Experimental: Treatment B
TPV capsule + RTV capsule + cocktail + digoxin injection
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 injection
Experimental: Treatment C
TPV solution + RTV capsule + cocktail + digoxin oral
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
Experimental: Treatment D
TPV solution + RTV capsule + cocktail + digoxin injection
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 injection



Primary Outcome Measures :
  1. Area under plasma concentration-time curve (AUC) at steady state [ Time Frame: up to 72 hours ]

Secondary Outcome Measures :
  1. Plasma concentration after 12 hours (Cp12h) [ Time Frame: 12 hours ]
  2. Maximum plasma concentration (Cmax) [ Time Frame: up to 12 hours ]
  3. Time of maximum concentration (Tmax) [ Time Frame: up to 72 hours ]
  4. Apparent terminal half-life (t1/2) [ Time Frame: up to 72 hours ]
  5. Area under plasma concentration-time curve (AUC) after single dose [ Time Frame: up to 72 hours ]
  6. Change in biomarkers [ Time Frame: baseline, up to 22 days ]
  7. Change in enzyme activity [ Time Frame: baseline, up to 22 days ]


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Additional Information:
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02243553     History of Changes
Other Study ID Numbers: 1182.101
First Posted: September 18, 2014    Key Record Dates
Last Update Posted: September 18, 2014
Last Verified: August 2014
Additional relevant MeSH terms:
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Vitamin K
Ritonavir
Tipranavir
polysaccharide-K
Digoxin
Midazolam
Dextromethorphan
Caffeine
Omeprazole
Warfarin
Pharmaceutical Solutions
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
HIV Protease Inhibitors