Industrial & Physical Pharmacy, Purdue University West Lafayette, Indiana, USA.
Industrial & Physical Pharmacy, Purdue University West Lafayette, Indiana, USA.
J Control Release. 2021 Sep 10;337:407-416. doi: 10.1016/j.jconrel.2021.07.043. Epub 2021 Jul 27.
Subcutaneously injected formulations have been developed for many biological products including monoclonal antibodies (mAbs). A knowledge gap nonetheless remains regarding the absorption and catabolism mechanisms and kinetics of a large molecule at the administration site. A multiscale pharmacokinetic (PK) model was thus developed by coupling multiphysics simulations of subcutaneous (SC) absorption kinetics with whole-body pharmacokinetic (PK) modeling, bridged by consideration of the presystemic clearance by the initial lymph. Our local absorption simulation of SC-injected albumin enabled the estimation of its presystemic clearance and led to the whole-body PK modeling of systemic exposure. The local absorption rate of albumin was found to be influential on the PK profile. Additionally, nineteen mAbs were explored via this multiscale simulation and modeling framework. The computational results suggest that stability propensities of the mAbs are correlated with the presystemic clearance, and electrostatic charges in the complementarity-determining region influence the local absorption rate. Still, this study underscores a critical need to experimentally determine various biophysical characteristics of a large molecule and the biomechanical properties of human skin tissues.
已经开发出许多生物制品的皮下注射制剂，包括单克隆抗体 (mAb)。然而，在给药部位，对于大分子的吸收和代谢机制以及动力学，仍存在知识空白。因此，通过将皮下 (SC) 吸收动力学的多物理场模拟与全身药代动力学 (PK) 建模相耦合，并通过考虑初始淋巴的系统性清除来桥接，开发了一种多尺度药代动力学 (PK) 模型。我们对 SC 注射白蛋白的局部吸收模拟能够估计其系统性清除，并导致全身暴露的全身 PK 建模。白蛋白的局部吸收速率被发现对 PK 曲线有影响。此外，通过这种多尺度模拟和建模框架还探索了 19 种 mAb。计算结果表明，mAb 的稳定性倾向与系统性清除有关，并且互补决定区中的静电电荷会影响局部吸收速率。尽管如此，这项研究强调了需要通过实验确定大分子的各种生物物理特性以及人体皮肤组织的生物力学特性的迫切需求。
