Effects of Steady State Tipranavir/Ritonavir or Darunavir/Ritonavir or Ritonavir on Platelet Function, Coagulation and Fibrinolysis Biomarkers in Healthy Subjects

Inclusion criteria

• Ability and willingness to give written informed consent to participate in this study (i.e., prior to any study-specific procedures)
• Age ≥18 years and ≤50 years
• Female subjects of child-bearing potential were eligible if:

• They had used a barrier contraceptive method for at least 12 weeks before administration of study medication and had a negative serum pregnancy test result during the screening period (Day - 35 to Day -3); or,
• Were abstinent for more than 12 weeks before screening and had a negative serum pregnancy test result during the screening period (Day -35 to Day -3); or,
• Had a documented tubal ligation and had a negative serum pregnancy test result during the screening period (Day -35 to Day -3)
• Ability to swallow capsules without difficulty
• Reasonable probability of completing the study
• Findings from medical history, physical examination and 12-lead ECG indicating subject was healthy and suitable for the trial in the opinion of the investigator
• Agreement to abstain from alcohol consumption or drugs of abuse during the study
• Agreement to abstain from ingestion of grapefruit, grapefruit juice, Seville oranges, or orange marmalade from screening period to the end of the study
• Negative urine drug screen for drugs of abuse
• Non smoker
• Agreement to abstain from use of tobacco products from screening period to the end of the study
• Negative HIV-1 serology by ELISA testing
• Negative Hepatitis B surface Antigen test (HBsAg)
• Negative Hepatitis C Virus antibody (anti-HCV) test by Enzyme Immunoassay
• Platelet count ≥125,000/mm3
• Hemoglobin ≥11.0 g/dL
• Prothrombin time ≤1.0 x upper limit of normal (ULN)
• Activated Partial thromboplastin time ≤1.0 x ULN

Exclusion criteria

• Female subjects who:

• had a positive serum pregnancy test during the screening period (Day -35 to Day -3) or during the study
• were breast feeding or planing to breast feed at any time from the screening period through 30 days after the last dose of the study drug
• were not willing to use a barrier method of contraception at any time from screening period through 30 days after the last dose of the study drug
• were taking any hormonal therapy for any reason such as birth control or replacement therapy
• Had used any investigational agent within 30 days prior to Visit 2
• Blood or plasma donations (>100 mL total) for research or altruistic reasons within 30 days prior to Visit 2
• Had used aspirin or any non-steroidal anti-inflammatory agent (NSAID), and including COX-2 inhibitors, dipyridamole, clopidogrel, ticlopidine or other antiplatelet drugs within 14 days prior to Visit 2 or during the study
• Active peptic ulceration or history of peptic ulcer disease
• Known history of or suspected hypersensitivity to aspirin, any NSAID or any other component of the test drugs (Tipranavir, Darunavir, Ritonavir)
• Known hypersensitivity to antiretroviral drugs (marketed or experimental drug in clinical research studies)
• Active bleeding disorder or history of active bleeding disorder
• Active Intra cranial hemorrhage (ICH) or history of ICH
• Active coronary artery disease or history of coronary artery disease
• Alcohol abuse (more than 60 g/day)
• Any indication for current use of aspirin or any NSAID or indication for such use from Visit 2 to Visit 18
• Had used any over-the-counter medication within 7 days prior to Visit 2, or current use of any prescription drug
• Subjects who had an abnormal laboratory result of Grade 1 or greater, as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS), (result must have been available at least 3 days prior to Visit 2-Day 1), except the following screening laboratory values:

• serum potassium, serum sodium, serum phosphate and uric acid, where central laboratory reference ranges will be used to determine eligibility rather than DAIDS table; or,
• amylase or creatinine results of Grade 1 on DAIDS table if these results are considered clinically not significant by investigator; or
• other marginally abnormal laboratory values not considered clinically significant by investigator and approved by clinical monitor
• History of any illness that in the opinion of the investigator might confound the results of the study or pose additional risks in administering aspirin, Tipranavir, Darunavir, or Ritonavir
• Hypersensitivity to sulphonamide drugs
• Had used proton pump inhibitors during 14 days prior to Visit 2
• Vitamin E intake in excess of 60 mg/day within 30 days prior to Visit 2
• Vitamin E supplementation in excess of 60 mg/day during the study (Vitamin E content of multivitamin tablets is allowed)