Tipranavir/Ritonavir Low Dose Pharmacokinetics in Treatment Naive Patients

• Area Under the Curve(AUC) of Tipranavir 24 h for Once Daily (QD) and AUC 12 h for Twice Daily (BID) [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  Tipranavir (TPV) pharmacokinetics
• Concentration-24 Hour (hr) Post Dose of Tipranavir - (Cp 24 h for QD and 12 hr Post Dose (CP 12h) for BID [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  TPV pharmacokinetics
• Trough Concentration (Cmin) of Tipranavir [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  TPV pharmacokinetics
• Maximum Concentration (Cmax) of Tipranavir [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  TPV pharmacokinetics
• Viral Load (log10 Copies/mL) Change From Baseline (Last Observation Carried Forward (LOCF)) [ Time Frame: Baseline (Day 0) to Final (Day 14) ]

• Apparent Oral Clearance I(Cl/F) of Tipranavir [ Time Frame: Final (Day 14) ]
  Tipranavir pharmacokinetics - Clearance 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.
• Volume of Distribution (V/F) of Tipranavir [ Time Frame: Final (Day 14) ]
  Tipranavir pharmacokinetics
• Terminal Half-Life (t1/2) of Tipranavir [ Time Frame: Final (Day 14) ]
  Tipranavir pharmacokinetics
• Time to Cmax (Tmax) of Tipranavir [ Time Frame: Final (Day 14) ]
  Tipranavir pharmacokinetics
• AUC 24 of Ritonavir for QD and AUC 12 of Ritonavir for BID [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  Ritonavir pharmacokinetics
• Cp 24 h of Ritonavirfor QD and CP 12 h of Ritonavir for BID [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  Ritonavir pharmacokinetics
• Apparent Oral Clearance I(Cl/F) of Ritonavir [ Time Frame: Final (Day 13 for QD, Day 14 for BID) ]
  Ritonavir pharmacokinetics
• Volume of Distribution (V/F) of Ritonavir [ Time Frame: Final (Day 14) ]
  Ritonavir pharmacokinetics
• Terminal Half-Life (t1/2) of Ritonavir [ Time Frame: Final (Day 14) ]
  Ritonavir pharmacokinetics
• Tmax of Ritonavir [ Time Frame: Final (Day 14) ]
  Ritonavir pharmacokinetics
• Cmax of Ritonavir [ Time Frame: Visits baseline, 5, 7, 9 and 13 or 14 ]
  Ritonavir pharmacokinetics

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

• Drug: tipranavir
• Drug: ritonavir

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).