JAC Advance Access originally published online on December 21, 2007
Journal of Antimicrobial Chemotherapy 2008 61(2):394-399; doi:10.1093/jac/dkm486
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Original research |
Significant effects of tipranavir on platelet aggregation and thromboxane B2 formation in vitro and in vivo
1 Pharmazentrum Frankfurt, Institute of Clinical Pharmacology at the Johann Wolfgang Goethe University Frankfurt, Germany 2 Infectiologicum Frankfurt, Frankfurt, Germany 3 HIVCENTER, Medical HIV Treatment and Research Unit at the Johann Wolfgang Goethe University Frankfurt, Germany
Received 5 September 2007; returned 22 November 2007; revised 13 November 2007; accepted 25 November 2007
* Corresponding author. Tel: +49-69-63016956; Fax: +49-69-63017636; E-mail: hentig{at}em.uni-frankfurt.de
Objectives: 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 (TPVconc) in vitro of up to 100 000 ng/mL. Platelet aggregation was stimulated either with 2 µM ADP (ADP) or 10 mg/L collagen (COL). TPVconc were measured with validated EPI-LC-MS/MS. Intraindividual comparisons of values at time points and TPVconc, respectively, were carried out with repeated samples ANOVA.
Results: Platelet aggregation (mean, maximal light transmission Amax) 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) TPVconc of 62 500 ng/mL (22 990–67 500). These results could be reproduced in vitro at TPVconc 50 000 ng/mL (AmaxADP/AmaxCOL = 20.7/36.9%; P = 0.003/<0.001) and 100 000 ng/mL (AmaxADP/AmaxCOL = 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 TPVconc 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.
Keywords: HIV protease inhibitors , HIV therapy , platelet function , thromboxane formation , intracranial haemorrhage
These authors contributed equally to the work.