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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: TPV low 2; Drug: TPV medium; Drug: TPV high 1; Drug: TPV low 1; Drug: TPV high 2; Drug: Ritonavir high; Drug: RTV low; Drug: Radiolabelled erythromycin

• Registration Number: NCT02251132
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2000-10
• Primary Completion: 2000-12
• Status Verified: 2014-09
• Study First Submitted: 2014-09-25
• Study First Submitted QC: 2014-09-25
• Last Update Submitted: 2014-09-25
• Study First Posted: 2014-09-29
• Last Update Posted: 2014-09-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 113

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TPV/RTV Low 3	TPV low 2	-
TPV/RTV Medium 2	TPV medium	-
TPV/RTV High 1	TPV high 1	-
TPV/RTV High 1	Radiolabelled erythromycin	-
TPV/RTV High 2	TPV high 1	-
TPV/RTV Low 1	TPV low 1	-
TPV/RTV Low 1	Ritonavir high	-
TPV/RTV Low 1	Radiolabelled erythromycin	-
TPV/RTV Low 2	TPV low 2	-
TPV/RTV Low 3	Radiolabelled erythromycin	-
TPV/RTV Medium 1	TPV medium	-
TPV/RTV Medium 2	Ritonavir high	-
TPV/RTV High 1	RTV low	-
TPV/RTV High 2	Radiolabelled erythromycin	-
TPV/RTV Medium 1	RTV low	-
TPV/RTV Medium 2	Radiolabelled erythromycin	-
TPV/RTV High 2	Ritonavir high	-
TPV/RTV Low 2	Radiolabelled erythromycin	-
TPV/RTV Low 3	Ritonavir high	-
TPV/RTV High 3	TPV high 2	-
TPV/RTV High 3	Ritonavir high	-
TPV/RTV Low 2	RTV low	-
TPV/RTV Medium 1	Radiolabelled erythromycin	-
TPV/RTV High 3	Radiolabelled erythromycin	-

Primary Outcome Measures

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

Secondary Outcome Measures

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