title: Significant effects of tipranavir on platelet aggregation and thromboxane B2 formation in vitro and in vivo.
abstract: OBJECTIVE
  In the past, bleeding events have been described for patients with haemophilia taking HIV-1 protease inhibitors. Recently, the FDA published a warning concerning intracranial haemorrhage in patients taking the HIV-1 protease inhibitor tipranavir co-administered with ritonavir.
  
  
  METHODS
  We investigated (i) platelet aggregation in vivo in HIV-1-infected adult patients (n = 5) immediately before and 2 and 4 h after dosing of tipranavir/ritonavir 500/200 mg. To further characterize the effects, we then evaluated (ii) platelet aggregation and (iii) thromboxane B2 (TxB2) formation (ELISA) with increasing tipranavir concentrations (TPV(conc)) in vitro of up to 100,000 ng/mL. Platelet aggregation was stimulated either with 2 microM ADP (ADP) or 10 mg/L collagen (COL). TPV(conc) were measured with validated EPI-LC-MS/MS. Intraindividual comparisons of values at time points and TPV(conc), respectively, were carried out with repeated samples ANOVA.
  
  
  RESULTS
  Platelet aggregation (mean, maximal light transmission A(max)) was significantly decreased in patients 4 h post-dose in collagen- (from 79.8% to 57.1%; P < 0.001) and in ADP-stimulated (from 58.5% to 54.0%; not significant) samples at a median (range) TPV(conc) of 62 500 ng/mL (22,990-67,500). These results could be reproduced in vitro at TPV(conc) 50,000 ng/mL (A(max)ADP/A(max)COL = 20.7/36.9%; P = 0.003/<0.001) and 100 000 ng/mL (A(max)ADP/A(max)COL = 14.5/17.1%; P < 0.001/<0.001). Median (range) TxB2 concentrations were reduced (P = 0.07) from 327 ng/mL (187-500) at baseline to 265 ng/mL (152-428) at 5000 ng/mL and were significantly reduced (P < 0.001) to 187 ng/mL (81-362) at a TPV(conc) of 50,000 ng/mL, respectively.
  
  
  CONCLUSIONS
  Five HIV-1-infected patients on tipranavir-containing highly active antiretroviral therapy presented marked decreases in platelet aggregation. In vitro these effects were reproduced and decreased TxB2 formation was also demonstrated. Inhibition of platelet aggregation while receiving tipranavir treatment might contribute to increased risk of bleeding.
authors.affiliation: Pharmazentrum Frankfurt, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Graff
authors.forename: Nils
authors.initials: N
authors.lastname: von Hentig
authors.forename: Karina
authors.initials: K
authors.lastname: Kuczka
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Peter
authors.initials: P
authors.lastname: Gute
authors.forename: Stefan
authors.initials: S
authors.lastname: Klauke
authors.forename: Errol
authors.initials: E
authors.lastname: Babacan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Harder
mesh_terms: D000328:Adult; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides; D013929:Thromboxane B2 / Q000097:blood*
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D013929:Thromboxane B2; C107201:tipranavir