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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Tipranavir; Drug: Ritonavir; Drug: 14C-Tipranavir

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Healthy HIV-negative male subjects as determined by results of screening. Healthiness was determined by medical history, laboratory testing and 12-lead ECG
2. Signed written informed consent in accordance with Good Clinical Practice (GCP)
3. Age >18 and <=60 years
4. Subjects within 20% of the normal height: weight range defined by the Metropolitan Life Insurance Company Tables
5. Ability to swallow numerous large capsules
6. 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:

1. Any finding of the medical examination (including blood pressure, pulse rate, and ECG) deviating from normal and of clinical relevance
2. History of clinically significant disease including metabolic, endocrinologic, immunological, hepatic, renal, gastrointestinal, respiratory, cardiovascular, psychiatric or neurological
3. History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator and/or the sponsor
4. Subjects with a history of drug abuse or alcoholism
5. Chronic or relevant acute (within 2 weeks of screening) infections
6. Subjects who have taken prescription medications, over-the-counter drugs, or herbal preparations within 2 weeks of the start of the trial
7. Participation in another trial with an investigational drug (in the 30 days prior to screening)
8. Blood donation >400 mL (within 1 month prior to treatment administration or during the trial)
9. Any laboratory value that represents a Division of DAIDS (DAIDS) toxicity Grade >1
10. Positive urine drug screen, positive HIV antibody, positive Hepatitis C Ribonucleic acid (RNA), or positive Hepatitis B surface antigen
11. History of any familial bleeding disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (Actual): July 1, 2003

Study Registration Dates

• First Submitted: September 25, 2014
• First Submitted That Met QC Criteria: September 29, 2014
• First Posted (Estimate): October 1, 2014

Study Record Updates

• Last Update Posted (Estimate): October 1, 2014
• Last Update Submitted That Met QC Criteria: September 29, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Tipranavir
• Other Study ID Numbers: 1182.24