Pharmacokinetics of Tipranavir Soft Elastic Capsules (SEDDS) and Ritonavir and Their Effects on Cytochrome P-450 (3A4) in Healthy Volunteers

An Open-label, Parallel Group, Multiple-dose Investigation of the Pharmacokinetics of Tipranavir Soft Elastic Capsules SEDDS and Ritonavir Soft Gel Capsules and Their Effects on Cytochrome P-450 (3A4) Activity in Normal Healthy Volunteers

The objective of this study is to establish the tipranavir-ritonavir steady-state dose-exposure relationships when administered on a b.i.d. dosing regimen; to determine the effects of tipranavir (TPV) and ritonavir (RTV) on cytochrome P-450 (CYP3A4) activity; to establish the dependency of the TPV M1 metabolite on RTV co-administration. Additionally, the short-term safety and tolerance of this drug combination will be evaluated.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: TPV low 1; Drug: Ritonavir high; Drug: Radiolabelled erythromycin; Drug: TPV low 2; Drug: RTV low; Drug: TPV medium; Drug: TPV high 1; Drug: TPV high 2

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female between 18 and 75 years of age inclusive
• Female subjects of child-bearing potential are required to use a barrier contraceptive method for at least 3 months prior to administration of study medication, during study medication administration and for 30 days after the end of the study
• Ability to swallow numerous large capsules without difficulty
• A body mass index (BMI) between 19 and 29 kg/m2
• Signed informed consent prior to trial participation
• Reasonable probability for completion of the study
• Acceptable screening laboratory values that indicate adequate baseline organ function are required at the time of screening. Laboratory values are considered to be acceptable if severity is no higher than Grade 1 based on the AIDS Clinical Trials Group (ACTG) Grading Scale. All laboratory values > Grade 1 are subject to approval by the BIPI clinical monitor
• Acceptable medical history, physical examination, electrocardiogram, and chest X-ray are required prior to entering the treatment phase of the study
• Willingness to abstain from alcohol for 48 hours prior to study Day 0 and abstain from alcohol for the duration of the study
• Willingness to abstain from ingesting grapefruit or grapefruit juice for the duration of the study
• Urine drug screen negative for drugs of abuse
• Negative HIV serology
• Negative for Hepatitis B surface antigen and Hepatitis C antibody

Exclusion Criteria:

• Female subjects who:

  • have a positive serum pregnancy test at Visits 1 or 2 OR
  • are breastfeeding
• Receipt of any other investigational medicine for 30 days prior to Day 0
• Receipt of any known enzyme altering drug for 30 days prior to Day 0, grapefruit and grapefruit juice within 15 days prior to Day 0 and antibiotics within 10 days prior to Day 0
• Excessive cigarette smoking, defined as greater than 10 cigarettes per day
• Blood or plasma donation within 30 days prior to Day 0
• Subjects with a seated systolic blood pressure either < 100 mg Hg or > 150 mm Hg; resting heart rate either < 50 beats/min or > 90 beats/min
• Subjects with a history of any illness or allergy that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering tipranavir or ritonavir to the subject
• Subjects who have had an acute illness within 2 weeks prior to Day 0
• Subjects who are currently taking any over-the-counter drug within 7 days prior to Day 0, or who are currently taking any prescription drug that, in the opinion of the investigator in consultation with the BIPI medical monitor and pharmacokineticist, might interfere with either the absorption, distribution or metabolism of the test substances
• Hypersensitivity to tipranavir, ritonavir or sulfonamide containing drugs
• Evidence of active substance abuse that, in the investigator's opinion, could affect study adherence

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPV/RTV Low 1	Drug: TPV low 1; Drug: Ritonavir high; Drug: Radiolabelled erythromycin
Experimental: TPV/RTV Low 2	Drug: Radiolabelled erythromycin; Drug: TPV low 2; Drug: RTV low
Experimental: TPV/RTV Low 3	Drug: Ritonavir high; Drug: Radiolabelled erythromycin; Drug: TPV low 2
Experimental: TPV/RTV Medium 1	Drug: Radiolabelled erythromycin; Drug: RTV low; Drug: TPV medium
Experimental: TPV/RTV Medium 2	Drug: Ritonavir high; Drug: Radiolabelled erythromycin; Drug: TPV medium
Experimental: TPV/RTV High 1	Drug: Radiolabelled erythromycin; Drug: RTV low; Drug: TPV high 1
Experimental: TPV/RTV High 2	Drug: Ritonavir high; Drug: Radiolabelled erythromycin; Drug: TPV high 1
Experimental: TPV/RTV High 3	Drug: Ritonavir high; Drug: Radiolabelled erythromycin; Drug: TPV high 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Trough plasma concentration at steady state (Cmin,ss)	up to 24 hours
Maximum plasma concentration at steady state (Cmax,ss)	up to 24 hours
Time of maximum concentration (tmax)	up to 24 hours
Area under the plasma concentration time curve from 0 to 12 hours (AUC0-12)	up to 12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with adverse events		up to 32 days
Oral clearance (Cl/F)		up to 24 hours
Apparent terminal half life (t1/2)		up to 24 hours
Percent of erythromycin metabolized per hour	Erythromycin breath test (ERMBT)	up to 24 hours
Number of subjects with clinically significant findings in laboratory tests		up to 32 days

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2000
• Primary Completion (Actual): December 1, 2000

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Estimate): September 29, 2014
• Last Update Submitted That Met QC Criteria: September 25, 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; Gastrointestinal Agents; Protease Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Erythromycin stearate; Ritonavir
• Other Study ID Numbers: 1182.5