Department of Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, Uppsala, Sweden.
CPT Pharmacometrics Syst Pharmacol. 2024 Oct;13(10):1630-1640. doi: 10.1002/psp4.13159. Epub 2024 Sep 16.
Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.
患有严重且有时为中度血友病 B 的患者预防性地接受因子 IX 浓缩物治疗，以预防出血。目前，有多种延长的末端半衰期 (EHL) 重组因子 IX 浓缩物可供使用，与标准半衰期重组 FIX(rFIX) 相比，在预防治疗中可减少给药频率。特别是重组 FIX-Fc 融合蛋白(rFIXFc；Alprolix®)表现出快速分布相，这可能是由于与血管外空间中的 IV 型胶原 (Col4) 结合所致。研究表明，血管外 rFIXFc 的存在具有防止出血的作用，因为在没有可测量的血浆 FIX 活性的情况下，不会发生额外的出血。我们在本研究中描述的 rFIXFc 的基于生理学的药代动力学 (PBPK) 模型能够准确预测 rFIXFc 在血浆中的观察到的浓度-时间曲线，并能够量化男性人群中静脉内给予 50IU/kg rFIXFc 后 rFIXFc 与 Col4 在血管外空间的结合。我们的模型预测，与 rFIXFc 在血浆中的 AUC 相比，与 Col4 结合的 rFIXFc 的总 AUC 约高 19 倍。这表明血管外隔室中存在的 rFIXFc 可能在 rFIXFc 给药后实现止血方面发挥重要作用。需要进一步研究 rFIXFc 的血管外分布和其他 EHL-FIX 浓缩物的分布谱，以评估我们的 PBPK 模型的预测，并研究其临床相关性。
