AMGEN, Thousand Oaks, California 91320, USA.
AAPS J. 2010 Dec;12(4):646-57. doi: 10.1208/s12248-010-9222-0. Epub 2010 Aug 25.
Hepcidin is a key regulator responsible for systemic iron homeostasis. A semi-mechanistic PK model for hepcidin and a fully human anti-hepcidin monoclonal antibody (Ab 12B9m) was developed to describe their total (free + bound) serum concentration-time data after single and multiple weekly intravenous or subcutaneous doses of Ab 12B9m. The model was based on target mediated drug disposition and the IgG-FcRn interaction concepts published previously. Both total Ab 12B9m and total hepcidin exhibited nonlinear kinetics due to saturable Fc-FcRn interaction. Ab 12B9m showed a limited volume of distribution and negligible linear elimination from serum. The nonlinear elimination of Ab 12B9m was attributed to the endosomal degradation of Ab 12B9m that was not bound to the FcRn receptor. The terminal half-life, assumed to be the same for free and total serum Ab 12B9m, was estimated to be 16.5 days. The subcutaneous absorption of Ab 12B9m was described with a first-order absorption rate constant k(a) of 0.0278 h⁻¹, with 86% bioavailability. The model suggested a rapid hepcidin clearance of approximately 800 mL h⁻¹ kg⁻¹. Only the highest-tested Ab 12B9m dose of 300 mg kg⁻¹ week⁻¹ was able to maintain free hepcidin level below the baseline during the dosing intervals. Free Ab 12B9m and free hepcidin concentrations were simulated, and their PK profiles were nonlinear as affected by their binding to each other. Additionally, the total amount of FcRn receptor involved in Ab 12B9m recycling at a given time was calculated empirically, and the temporal changes in the free FcRn levels upon Ab 12B9m administration were inferred.
亚铁调素是负责全身铁稳态的关键调节剂。建立了一个亚铁调素的半机械性 PK 模型和一个全人源抗亚铁调素单克隆抗体（Ab12B9m）的完整模型，以描述 Ab12B9m 单次和每周多次静脉或皮下给药后它们的总（游离+结合）血清浓度-时间数据。该模型基于先前发表的靶向介导药物处置和 IgG-FcRn 相互作用的概念。由于 Fc-FcRn 相互作用饱和，总 Ab12B9m 和总亚铁调素均表现出非线性动力学。Ab12B9m 显示出有限的分布容积，从血清中几乎没有线性消除。Ab12B9m 的非线性消除归因于未与 FcRn 受体结合的 Ab12B9m 的内体降解。假设游离和总血清 Ab12B9m 的半衰期相同，半衰期估计为 16.5 天。Ab12B9m 的皮下吸收用一级吸收速率常数 k(a)为 0.0278 h⁻¹来描述，具有 86%的生物利用度。该模型表明亚铁调素的清除速度很快，约为 800 mL h⁻¹ kg⁻¹。只有最高测试剂量的 300 mg kg⁻¹ week⁻¹能够在给药间隔内将游离亚铁调素水平维持在基线以下。模拟了游离 Ab12B9m 和游离亚铁调素的浓度，它们的 PK 曲线受到彼此结合的影响呈非线性。此外，还根据经验计算了在给定时间内参与 Ab12B9m 再循环的 FcRn 受体总量，并推断了 Ab12B9m 给药后游离 FcRn 水平的时间变化。
