Tipranavir/Ritonavir Low Dose Pharmacokinetics in Treatment Naive Patients

Study Overview
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Brief Summary
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The purpose of this study is to identify an optimal dose combination(s) of tipranavir (TPV) and ritonavir (RTV) for antiretroviral treatment naïve HIV-1 infected patients that can be used in pivotal trial by assessing the steady-state pharmacokinetics and short-term efficacy and safety

Official Title
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A Multicenter, Randomized, Open Label, Clinical Trial to Evaluate Three Doses of Tipranavir Boosted With Ritonavir (500 mg/200 mg qd, 250 mg/100 mg Bid and 500 mg/100 mg Bid) by Assessing the Steady-state Pharmacokinetics and Short-term Efficacy and Safety in HIV-1 Positive Treatment naïve Patients

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: tipranavir
* Drug: ritonavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent in accordance with GCP and local regulatory requirements prior to trial participation. HIV-1 infected men and non-pregnant women who are treatment naïve, with positive serology (EIA) confirmed by Western blot. Age > 18 and < 65 years. CD4 > 200 cells/mm3 Viral load (HIV-1 mRNA viral load) > 5,000 copies/mL. Ability to swallow multiple large capsules without difficulty. 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 2, based on the DAIDS/ACTG Grading Scale (see Appendix 10.2). Acceptable medical history, physical examination, and 12-lead ECG at screening Willingness to abstain from the following starting 2 weeks prior to administration of any study medication and up until the end of the study: o Grapefruit or grapefruit juice, Seville oranges, St. John's Wort, and Milk Thistle. Willingness to abstain from alcohol 3 days prior to administration of any study medication up to the end of the study. Willingness to abstain from the following starting 3 days prior to PK sampling: o Garlic supplements and methylxanthine containing foods or drinks (including coffee, tea, cola, energy drinks, chocolate, etc.). Willingness to abstain from over-the-counter herbal medications for the duration of the study. Willingness to abstain from any over the counter medication 7 days prior to administration of any study medication (including vitamins, minerals, dietary supplements and antacids) during the study until completion of the post study assessments. Exclusion Criteria: Female patients 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. Suspected or documented seroconversion within last 6 months Participation in another trial with an investigational medicine within 2 months prior to Day 0 of this study. Use of any pharmacological contraceptive (including oral, patch or injectable contraceptives) within 1 month prior to Day 0 and for the duration of the study. Use of hormone replacement therapy within 1 month prior to Day 0 and anytime during the study. History of acute illness within 30 days prior to Day 0. Have evidence of active or acute HBV or HCV. Alcohol or substance abuse within 1 year prior to screening or during the study. Patients 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. Patients who have taken (within 7 days prior to Day 0) any over-the-counter or prescription medication that, in the opinion of the investigator in consultation with the BI clinical monitor, might interfere with absorption, distribution, or metabolism of the study medications. Known hypersensitivity to any ingredients of the test drug. Inability to adhere to the protocol. Genotypic resistance to tipranavir (defined as a TPV mutation score > 4).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: tipranavir|nan|
|Drug: ritonavir|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral Load (log10 Copies/mL) Change From Baseline (Last Observation Carried Forward (LOCF)) |  | Baseline (Day 0) to Final (Day 14) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apparent Oral Clearance I(Cl/F) of Tipranavir | Tipranavir pharmacokinetics - Clearance (CL) is defined as the dose of a drug divided by the area-under-the-concentration-time curve (AUC), ie. CL = Dose / AUC. For extravascu-lar models the fraction of dose absorbed cannot be estimated, therefore clear-ance for these models is actually Cl/F where F is the fraction of the drug dose which is absorbed. | Final (Day 14) | 
| Area Under the Curve(AUC) of Tipranavir 24 h for Once Daily (QD) and AUC 12 h for Twice Daily (BID) | Tipranavir (TPV) pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Concentration-24 Hour (hr) Post Dose of Tipranavir - (Cp 24 h for QD and 12 hr Post Dose (CP 12h) for BID | TPV pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Trough Concentration (Cmin) of Tipranavir | TPV pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Maximum Concentration (Cmax) of Tipranavir | TPV pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Volume of Distribution (V/F) of Tipranavir | Tipranavir pharmacokinetics | Final (Day 14) | 
| Terminal Half-Life (t1/2) of Tipranavir | Tipranavir pharmacokinetics | Final (Day 14) | 
| Time to Cmax (Tmax) of Tipranavir | Tipranavir pharmacokinetics | Final (Day 14) | 
| AUC 24 of Ritonavir for QD and AUC 12 of Ritonavir for BID | Ritonavir pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Cp 24 h of Ritonavir for QD and CP 12 h of Ritonavir for BID | Ritonavir pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Apparent Oral Clearance I(Cl/F) of Ritonavir | Ritonavir pharmacokinetics | Final (Day 13 for QD, Day 14 for BID) | 
| Volume of Distribution (V/F) of Ritonavir | Ritonavir pharmacokinetics | Final (Day 14) | 
| Terminal Half-Life (t1/2) of Ritonavir | Ritonavir pharmacokinetics | Final (Day 14) | 
| Tmax of Ritonavir | Ritonavir pharmacokinetics | Final (Day 14) | 
| Cmax of Ritonavir | Ritonavir pharmacokinetics | Visits baseline, 5, 7, 9 and 13 or 14 | 
| Clinical Abnormal Findings in Laboratory and Physical Examination |  | Screening through the end of the study (14 days) |