title: Effects of tipranavir, darunavir, and ritonavir on platelet function, coagulation, and fibrinolysis in healthy volunteers.
abstract: The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days. In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA-100® closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA-induced platelet aggregation.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. Jens.Kort@boehringer-ingelheim.com
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Kort
authors.forename: Stella
authors.initials: S
authors.lastname: Aslanyan
authors.forename: Joseph
authors.initials: J
authors.lastname: Scherer
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.forename: Veronika
authors.initials: V
authors.lastname: Kohlbrenner
authors.forename: Patrick
authors.initials: P
authors.lastname: Robinson
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000187:drug effects; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D011446:Prospective Studies; D011725:Pyridines / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D001779:Blood Coagulation Factors; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir; C107201:tipranavir