کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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3028419 | 1183009 | 2011 | 5 صفحه PDF | دانلود رایگان |
IntroductionBleeding episodes in haemophilia patients with inhibitors are primarily treated with by-passing agents such as recombinant activated FVII (rFVIIa). Prophylactic treatment with rFVIIa has been shown to significantly reduce the number of bleeding episodes as compared to conventional on-demand haemostatic therapy, and a reduced dosing frequency could present an improved treatment option in inhibitor patients.Materials and methodsA series of glycoPEGylated rFVIIa derivatives (5-40 K PEG) has been produced and their effect and pharmocokinetics have been investigated in several animal species.ResultsThe glycoPEGylated rFVIIa derivatives exhibit significant prolongation of half-life in mice, dogs and pigs as measured by rFVIIa clot activity. The clearance of rFVIIa, rFVIIa-5 K PEG, rFVIIa-10 K PEG, rFVIIa-20 K PEG and rFVIIa-40 K PEG in minipigs were estimated to 59, 27, 22, 8.7 and 3.1 ml/h/kg, respectively. Across species a reduction in clearance as a function of the size of the attached PEG was observed. By allometric scaling, the compiled pharmacokinetics predicts a human half-life for rFVIIa-10 K PEG and rFVIIa-40 K PEG of approximately 7 and 12 h, respectively. The rFVIIa-10 K PEG and rFVIIa-40 K PEG are efficacious in stopping a bleed in the haemophilia A mouse tail-bleeding model after intravenous administration.ConclusionsGlycoPEGylation of rFVIIa significantly increases the rFVIIa exposure in three animal models, glycoPEGylated rFVIIa compounds are effective in vivo and thus, represents a potential prophylactic treatment option for patients with inhibitors.
Journal: Thrombosis Research - Volume 128, Issue 2, August 2011, Pages 191–195