Stader Felix, Liu Cong, Derbalah Abdallah, Momiji Hiroshi, Pan Xian, Gardner Iain, Jamei Masoud, Sepp Armin
Simcyp Division, Certara UK Ltd., Level 2 Acero, 1 Concourse Way, Sheffield S1 2BJ, UK.
Antibodies (Basel). 2024 Aug 15;13(3):70. doi: 10.3390/antib13030070.
The bioavailability of a monoclonal antibody (mAb) or another therapeutic protein after subcutaneous (SC) dosing is challenging to predict from first principles, even if the impact of injection site physiology and drug properties on mAb bioavailability is generally understood. We used a physiologically based pharmacokinetic model to predict pre-systemic clearance after SC administration mechanistically by incorporating the FcRn salvage pathway in antigen-presenting cells (APCs) in peripheral lymph nodes, draining the injection site. Clinically observed data of the removal rate of IgG from the arm as well as its plasma concentration after SC dosing were mostly predicted within the 95% confidence interval. The bioavailability of IgG was predicted to be 70%, which mechanistically relates to macropinocytosis in the draining lymph nodes and transient local dose-dependent partial saturation of the FcRn receptor in the APCs, resulting in higher catabolism and consequently less drug reaching the systemic circulation. The predicted free FcRn concentration was reduced to 40-45%, reaching the minimum 1-2 days after the SC administration of IgG, and returned to baseline after 8-12 days, depending on the site of injection. The model predicted the uptake into APCs, the binding affinity to FcRn, and the dose to be important factors impacting the bioavailability of a mAb.
单克隆抗体（mAb）或其他治疗性蛋白皮下（SC）给药后的生物利用度很难从基本原理进行预测，即便注射部位生理学和药物特性对mAb生物利用度的影响已得到普遍认识。我们使用了基于生理学的药代动力学模型，通过纳入外周淋巴结中抗原呈递细胞（APC）的FcRn挽救途径，从机制上预测SC给药后的首过清除率。临床观察到的SC给药后IgG从手臂的清除率及其血浆浓度数据大多在95%置信区间内得到预测。预测IgG的生物利用度为70%，这从机制上与引流淋巴结中的巨胞饮作用以及APC中FcRn受体的瞬时局部剂量依赖性部分饱和有关，从而导致更高的分解代谢，进而使进入体循环的药物减少。预测的游离FcRn浓度降至40 - 45%，在SC注射IgG后1 - 2天达到最低，8 - 12天后恢复至基线水平，这取决于注射部位。该模型预测，APC摄取、与FcRn的结合亲和力以及剂量是影响mAb生物利用度的重要因素。
