Effects of Steady-state Efavirenz 600 mg QD (Sustiva®) on Tipranavir Concentration at Steady-state in Healthy Adult Volunteers

A Single-centre, Open-label Study to Assess the Effects of Steady-state Efavirenz 600 mg QD (Sustiva®) on Tipranavir Concentration When Tipranavir/Ritonavir Are Administered at Doses 500 mg/200 mg BID to Steady-state in Healthy Adult Volunteers

Study to investigate the effects of steady-state Efavirenz (600 mg QD) on the steady-state pharmacokinetics of Tipranavir (500 mg BID) coadministered with Ritonavir (200 mg BID)

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Tipranavir; Drug: Ritonavir; Drug: Efavirenz

• Study Type: Interventional
• Enrollment (Actual): 34
• 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: All

Description

Inclusion Criteria:

1. Male or female subjects between 18 and 60 years of age inclusive
2. A Body Mass Index (BMI) between 18 and 29.9 kg/m2
3. Signed informed consent prior to trial participation
4. Ability to swallow multiple large capsules without difficulty

5. Acceptable laboratory values that indicate adequate baseline organ function at screening visit

   • Laboratory values are considered to be acceptable if the severity of any parameter is ≤Grade 1, based on the Division of AIDS (DAIDS)/AIDS Clinical Trials Group (ACTG) Grading Scale
   • All abnormal laboratory values >Grade 1 are subject to approval by the BI trial clinical monitor
6. Acceptable medical history, physical examination, and 12-lead ECG at screening

7. Willingness to abstain from the following starting 2 weeks prior to administration of any study medication and up until the end of the study:

   • Grapefruit or grapefruit juice, red wine, Seville oranges, St. John's Wort, and Milk Thistle
8. Willingness to abstain from alcohol starting 3 days prior to administration of any study medication up to the end of the study

9. Willingness to abstain from the following starting 3 days prior to pharmacokinetic (PK) sampling:

   • Garlic supplements and methylxanthine containing foods or drinks (including coffee, tea, cola, energy drinks, chocolate, etc.), apples or apple juice
10. Willingness to abstain from over-the-counter herbal medications for the duration of the study
11. Must be a non-smoker
12. Willingness to abstain from vigorous physical exercise during intensive PK days; Days 10 and 24
13. Reasonable probability for completion of the study

Exclusion Criteria:

1. Female subjects of reproductive potential who:

   • Have positive serum pregnancy test
   • Have not been using a barrier method of contraception for at least 3 months prior to participation in the study
   • Are not willing to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during and 60 days after completion/termination of the trial
   • Are breast-feeding.

2. Use of any pharmacological contraceptive (including oral, patch or injectable contraceptives) within 1 month prior to Day 1 and for the duration of the study.

   Due to long half-life, subjects using Depo-Provera® within six months prior to Day 1 will be excluded from participation in this study

3. Use of hormone replacement therapy within 1 month prior to Day 1 and anytime during the study
4. Participation in another trial with an investigational medicine within 2 months prior to Day 1 of this study
5. Use of any medication listed in Appendix 10.5 within 30 days prior to Day 1 of this study
6. Administration of antibiotics within 15 days prior to Day 1 and anytime during the study

7. History of acute illness within 60 days prior to Day 1

   • Subjects will be excluded for acute illnesses that occurred more than 60 days prior to Day 1 if, in the opinion of the investigator, the subject does not qualify as a healthy volunteer
8. Have serological evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV)
9. Have serological evidence of exposure to HIV
10. Alcohol or substance abuse within 1 year prior to screening or during the study
11. Blood or plasma donations within 30 days prior to Day 1 or during the study
12. 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 TPV, RTV or EFV to the subject
13. History of a psychiatric disorder that required pharmacological or other psychological treatment
14. Subjects who have taken (within 7 days prior to Day 1) any over-the-counter or prescription medication that, in the opinion of the investigator in consultation with the sponsor's clinical monitor, might interfere with absorption, distribution, or metabolism of the study medications
15. Known hypersensitivity to sulphonamide class of drugs
16. Known hypersensitivity to TPV, RTV, EFV or antiretroviral drugs (marketed or experimental use as part of clinical research studies)
17. Known elevated liver enzymes in past trials with any compound
18. Inability to adhere to the protocol
19. Cautions or warnings in the RTV and EFV package insert which, in the opinion of the investigator, constitute grounds for subject exclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TPV/RTV/EFV; tipranavir (TPV) + ritonavir (RTV) from day 1 to day 24 efavirenz (EFV) from day 10 to day 23	Drug: Tipranavir; Drug: Ritonavir; Drug: Efavirenz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under plasma concentration time curve from 0-12 hours (AUC0-12h)		up to 12 hours after drug administration
Maximum plasma concentration at steady state (Cmax)		up to 12 hours after drug administration
Drug concentration in plasma at 12 hours after administration (Cp12h)	Tipranavir (TPV)	up to 12 hours after drug administration
Last measured drug concentration in plasma (Cplast)	Ritonavir (RTV)	up to 12 hours after drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Trough plasma concentration (Cmin)	before drug administration
Time from dosing to the maximum concentration (tmax)	up to 12 hours after drug administration
Elimination half-life (t1/2)	up to 12 hours after drug administration
Oral clearance (CL/F)	up to 12 hours after drug administration
Volume of distribution (Vz/F)	up to 12 hours after drug administration
Number of subjects with adverse events	up to 38 days after first drug administration
Number of subjects with clinically significant findings in laboratory tests	up to 38 days after first drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): July 1, 2006

Study Registration Dates

• First Submitted: August 26, 2014
• First Submitted That Met QC Criteria: August 26, 2014
• First Posted (Estimate): August 27, 2014

Study Record Updates

• Last Update Posted (Estimate): August 27, 2014
• Last Update Submitted That Met QC Criteria: August 26, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Ritonavir; Tipranavir; Efavirenz
• Other Study ID Numbers: 1182.102