Effects of Steady-state TPV/RTV on the Single-dose Pharmacokinetics of Rifabutin and the Effects of Single-dose Rifabutin on the Steady-state Pharmacokinetics of TPV in Healthy Adult Volunteers

Phase 1

Completed

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

• Registration Number: NCT02251171
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

Study to determine the effects of steady-state Tipranavir (TPV) / Ritonavir (RTV) (500mg/200mg bid) on the single-dose pharmacokinetics of Rifabutin (RFB) and to determine the effects of single-dose RFB on the steady-state pharmacokinetics of TPV 500mg (co-administered with RTV 200mg)

Detailed Description

Not available

Study Timeline

• Study Start: 2003-08
• Primary Completion: 2003-10
• 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: 24

Inclusion Criteria

1. Male and female subjects between 18 and 60 years of age inclusive

2. A Body Mass Index (BMI) between 18 and 29 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 are required at the time of screening. Laboratory values are considered to be acceptable if severity was less than or equal to Grade 1, based on the AIDS Clinical Trials Group (ACTG) Grading Scale. All abnormal laboratory values greater than Grade 1 are subject to approval by the trial clinical monitor

6. Acceptable medical history, physical examination, and 12-lead ECG are required prior to entering the treatment phase of the study. The requirement for chest X-ray is left to the investigator's discretion

7. Willingness to abstain from the following starting 14 days prior to any administration of study drug up until the end of the study:

   • Grapefruit or grapefruit juice
   • Red wine
   • Seville oranges
   • St. John's Wort or Milk Thistle

8. Willingness to abstain from alcohol starting 2 days prior to administration of any study drug up to the end of the study

9. Willingness to abstain from the following within 72 hours of pharmacokinetic (PK) sampling:

   • Garlic supplements
   • Methylxanthine containing drinks (coffee, tea, cola, energy drinks, chocolate, etc.)

10. Willingness to abstain from over the counter herbal medications for the duration of the study

11. Have been non-smokers for 3 months

12. Willingness to abstain from vigorous physical exercise during intensive PK study Days 1, 14, and 15

13. Reasonable probability for completion of the study

Exclusion Criteria

As a guideline, subjects who have abnormal laboratory values at screening, and who are taking prescription medications are excluded:

1. Female subjects with reproductive potential who:

   • Have positive serum β-human chorionic gonadotropin at Visit 1, or on study Day 0 or study Day 1
   • Have not been using a barrier contraceptive method for at least 3 months prior to Visit 3 (study Day 1)
   • Are not willing to use a reliable method of barrier contraception (such as diaphragm with spermicidal cream/jelly or condoms with spermicidal foam), during the trial and 60 days after completion/termination
   • Are breast-feeding

2. Participation in another trial with an investigational medicine within 60 days prior to study Day 0 (Visit 2)

3. Use of any medication listed in Protocol within 30 days prior to study Day 0 (Visit 2)

4. Use of any pharmacological contraceptive (including oral, patch or injectable contraceptives) within 1 month prior to study Day 0 and for the duration of the study. Use of Depo-Provera is excluded for six months prior to study Day 0

5. Use of hormone replacement therapy within 1 month prior to study Day 0 and for the duration of the study

6. Administration of antibiotics within 10 days prior to study Day 0 (Visit 2) or during the trial

7. History of acute illness within sixty (60) days of study Day 0. Subjects are excluded if they have an acute illness greater than sixty days prior to study Day 0 if, in the opinion of the investigator, the subject did not qualify as a healthy volunteer

8. History of thrombotic disease

9. History of migraine headache

10. Have serological evidence of hepatitis B or C virus

11. Have serological evidence of exposure to HIV

12. Recent history of alcohol or substance abuse (within 1 year of screening)

13. Blood or plasma donations within 30 days prior to study Day 0 (Visit 2) or during the trial

14. Subjects with a seated systolic blood pressure either <100 mm Hg or >150 mm Hg; resting heart rate either <50 beats/min or >90 beats/min. For subjects with a resting heart rate below 50, or above 90, the investigator may discuss their exclusion with the clinical monitor on a case-by-case basis

15. Subjects with 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 RFB to the subject

16. Subjects who have taken (within 7 days prior to study Day 0) or are taking any over-the-counter or prescription drug that, in the opinion of the investigator in consultation with the clinical monitor, might interfere with either the absorption, distribution or metabolism of the test substances

17. Known hypersensitivity to TPV, RTV, RFB, or sulphonamide class of drugs

18. Inability to adhere to the protocol

19. Cautions or warnings in the RTV and RFB package insert which, in the judgment of the investigator, should exclude a subject

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TPV/RTV - Rifabutin	Tipranavir	Day 1: single dose Rifabutin Days 8-20: morning and evening doses of Tipranavir/Ritonavir Day 15: single dose Rifabutin
TPV/RTV - Rifabutin	Ritonavir	Day 1: single dose Rifabutin Days 8-20: morning and evening doses of Tipranavir/Ritonavir Day 15: single dose Rifabutin
TPV/RTV - Rifabutin	Rifabutin	Day 1: single dose Rifabutin Days 8-20: morning and evening doses of Tipranavir/Ritonavir Day 15: single dose Rifabutin

Primary Outcome Measures

Name	Time	Method
Area under plasma concentration time curve from 0-12 hours (AUC0-12h)	up to 12 hours after drug administration
Area under the plasma drug concentration-time curve from time zero to infinity of the analytes (AUC0-∞)	up to 144 hours after drug administration
Maximum plasma concentration of the analytes in plasma (Cmax)	up to 144 hours after drug administration
Drug concentration of the analytes in plasma at 12 hours after administration (Cp12h)	up to 12 hours after drug administration

Secondary Outcome Measures

Name	Time	Method
Oral clearance (CL/F)	up to 144 hours after drug administration
Number of subjects with adverse events	up to 24 days
Volume of distribution (V)	up to 144 hours after drug administration
Number of subjects with abnormal changes in laboratory parameters	up to 21 days
Time of maximum concentration (Tmax)	up to 144 hours after drug administration
Apparent terminal half life (t1/2)	up to 144 hours after drug administration