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

Abstract

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