Predicting monoclonal antibody pharmacokinetics following subcutaneous administration via whole-body physiologically-based modeling

摘要: Use of the subcutaneous (SC) route for administering monoclonal antibodies (mAbs) to treat chronic conditions has been hindered because an incomplete understanding fundamental mechanisms controlling mAb absorption from SC site, and due limited translatability preclinical studies. In this paper, we report on development evaluation a whole-body physiologically-based model predict pharmacokinetics following administration. The circulatory is based physiological processes governing transport includes two mAb-specific parameters representing differences in pinocytosis rate diffusive/convective rates among mAbs. At administration additional are used represent lymphatic capillary uptake pre-systemic clearance. Model employed clinical intravenous (IV) plasma PK data 20 mAbs 12 these mAbs, as obtained literature. resulting reliably described both IV measured concentration data. addition, metric positive charge across mAb's complementarity determining region vicinity was found positively correlate with model-based estimates parameter organ/tissue These relationships were incorporated into accurately predicted profiles three out four separate not included development. reported herein, provides platform characterize disposition humans.