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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Tipranavir; Drug: Ritonavir; Drug: Efavirenz

• Registration Number: NCT02226991
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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)

Detailed Description

Not available

Study Timeline

• Study Start: 2006-04
• Primary Completion: 2006-07
• Status Verified: 2014-08
• Study First Submitted: 2014-08-26
• Study First Submitted QC: 2014-08-26
• Last Update Submitted: 2014-08-26
• Study First Posted: 2014-08-27
• Last Update Posted: 2014-08-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 34

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TPV/RTV/EFV	Efavirenz	tipranavir (TPV) + ritonavir (RTV) from day 1 to day 24 efavirenz (EFV) from day 10 to day 23
TPV/RTV/EFV	Tipranavir	tipranavir (TPV) + ritonavir (RTV) from day 1 to day 24 efavirenz (EFV) from day 10 to day 23
TPV/RTV/EFV	Ritonavir	tipranavir (TPV) + ritonavir (RTV) from day 1 to day 24 efavirenz (EFV) from day 10 to day 23

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Time from dosing to the maximum concentration (tmax)	up to 12 hours after drug administration
Trough plasma concentration (Cmin)	before drug administration
Number of subjects with adverse events	up to 38 days after first 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 clinically significant findings in laboratory tests	up to 38 days after first drug administration