Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics

• Published in: Journal of controlled release Vol. 337; pp. 407 - 416
• Main Authors: Zheng, Fudan, Hou, Peng, Corpstein, Clairissa D., Park, Kinam, Li, Tonglei
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 10.09.2021
• Subjects: absorption; albumins; Bioavailability; biomechanics; Biotherapeutics; catabolism; lymph; mAb; Multiscale modeling; pharmacokinetics; Physiologically-based pharmacokinetics; Simulation; skin (animal); Subcutaneous absorption; Bioavailability; Multiscale modeling; ECM; mAb; Physiologically-based pharmacokinetics; SC; CDR; Biotherapeutics; Simulation; NMSE; mAbs; FcRn; PK; Subcutaneous absorption; TMDD; mPBPK
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2021.07.043

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. [Display omitted]