School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
Band Therapeutics, Lexington, Massachusetts, USA.
AAPS J. 2024 Jul 12;26(4):81. doi: 10.1208/s12248-024-00952-4.
Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.
缺乏凝血因子 VIII（FVIII）浓缩物是资源有限国家进行血友病 A 预防治疗的限制因素之一。Rondaptivon pegol（BT200）是一种聚乙二醇化的适体，在之前的研究中已显示可提高血管性血友病因子（VWF）和 FVIII 的水平。根据合理的假设，建立了 BT200 的群体药代动力学模型，并将其与 VWF 和 FVIII 的动力学模型相链接。所建立的 BT200 的 PK/PD 模型描述了在两项临床试验中健康志愿者和轻度至中度血友病 A 患者中 BT200、VWF 和 FVIII 的观察到的动力学。使用来自接受重组 FVIII 产品的重度血友病 A 患者的外部数据集评估了所建立的模型。所建立和评估的 PK/PD 模型能够描述和预测健康志愿者和血友病 A 患者中 BT200、VWF 和 FVIII 的浓度-时间曲线。随后，在虚拟重度血友病 A 患者中，根据不同的给药方案，预测了在给予血浆源性 FVIII 浓缩物和 BT200 后的 FVIII 浓度-时间曲线。与重组产品相比，含有 VWF 的血浆源性产品在资源有限的国家更容易获得。在没有和存在 BT200 的情况下，比较了一周内 FVIII 达到 1 和 3 IU/dL 以上的时间。每周一次给予 6 mg BT200 联合每周两次给予 10 IU/kg 血浆源性 FVIII 的组合剂量，与没有 BT200 时每周三次给予 30 IU/kg FVIII 的剂量保持相似的覆盖范围，每周仅为 FVIII 剂量的 22%。
