Pharmacokinetics of Tipranavir/Ritonavir and Its Metabolites in Healthy Male Subjects

Study Overview
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Brief Summary
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Study to evaluate the pharmacokinetics of Tipranavir and its metabolites including excretion and mass balance of parent compound and radioactivity at steady-state; to isolate, identify and quantify major metabolites of tipranavir in plasma, urine and feces

Official Title
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A Phase I Multiple Oral Dose Trial of Tipranavir 500 mg/Ritonavir 200 mg Dosed to Steady State Followed by Single-dose 14C-radiolabeled Tipranavir Co-administered With Tipranavir 500 mg/Ritonavir 200 mg to Characterize the Excretion Balance and Metabolite Profile of 14C-radiolabeled Tipranavir in Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: 14C-Tipranavir
* Drug: Tipranavir
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy HIV-negative male subjects as determined by results of screening. Healthiness was determined by medical history, laboratory testing and 12-lead ECG Signed written informed consent in accordance with Good Clinical Practice (GCP) Age >18 and <=60 years Subjects within 20% of the normal height: weight range defined by the Metropolitan Life Insurance Company Tables Ability to swallow numerous large capsules Willingness to abstain from smoking, ingesting methylxanthine containing drinks or food (coffee, tea, cola, chocolate, etc.), or ingesting alcohol, St. John's Wort, milk thistle, garlic supplements, Seville oranges, and grapefruit or grapefruit juice for the duration of the study Exclusion Criteria: Any finding of the medical examination (including blood pressure, pulse rate, and ECG) deviating from normal and of clinical relevance History of clinically significant disease including metabolic, endocrinologic, immunological, hepatic, renal, gastrointestinal, respiratory, cardiovascular, psychiatric or neurological History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator and/or the sponsor Subjects with a history of drug abuse or alcoholism Chronic or relevant acute (within 2 weeks of screening) infections Subjects who have taken prescription medications, over-the-counter drugs, or herbal preparations within 2 weeks of the start of the trial Participation in another trial with an investigational drug (in the 30 days prior to screening) Blood donation >400 mL (within 1 month prior to treatment administration or during the trial) Any laboratory value that represents a Division of DAIDS (DAIDS) toxicity Grade >1 Positive urine drug screen, positive HIV antibody, positive Hepatitis C Ribonucleic acid (RNA), or positive Hepatitis B surface antigen History of any familial bleeding disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Male

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPV/r followed by 14C-radiolabeled TPV<br>Tipranavir/Ritonavir dosed to steady state followed by single-dose 14C-radiolabeled tipranavir co-administered with Tipranavir/Ritonavir | Drug: 14C-Tipranavir<br> <br> Drug: Tipranavir<br> <br> Drug: Ritonavir<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radioactive levels of 14C-Tipranavir in plasma and blood |  | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Radioactive erythrocyte-plasma partition ratio |  | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Maximum measured concentration of the analyte in plasma (Cmax) | 14C-radiolabeled Tipranavir + Tipranavir | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Plasma concentration 12 hours after dosing (Cp12h) | 14C-radiolabeled Tipranavir + Tipranavir | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Area under plasma concentration time curve (AUC) | 14C-radiolabeled Tipranavir + Tipranavir | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Time of maximum concentration (Tmax) | 14C-radiolabeled Tipranavir + Tipranavir | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Apparent terminal half life (t1/2) | 14C-radiolabeled Tipranavir + Tipranavir | -10 minutes, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dose administration | 
| Cumulative amount of 14C- radioactivity in Urine and feces |  | up to 15 days | 
| Percent excretion in urine and feces | relative to total radioactivity administered | up to 15 days | 
| Time needed to achieve steady-state as determined by tipranavir trough concentrations |  | up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events |  | up to 15 days | 
| Number of subjects with abnormal changes in laboratory parameters |  | up to day 14 | 
| Number of subjects with clinically significant changes in Electrocardiogram (ECG) |  | up to day 6 |