Significant effects of tipranavir on platelet aggregation and thromboxane B2 formation in vitro and in vivo.
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.
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*
D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D013929:Thromboxane B2; C107201:tipranavir