A Tutorial on the Development of a Physiologically Inspired PKRO Model for Monoclonal Antibodies.

Modeling and simulations are indispensable tools to describe pharmacokinetics (PK) and pharmacodynamics to support monoclonal antibody (mAb) development. The linear PK of mAbs is commonly described by a 2-compartment PK model, while the nonlinear PK often observed at low doses is described by target mediated drug disposition (TMDD) models. Since target binding is the primary pharmacology of mAbs and receptor occupancy (RO) could impact PK through TMDD, it is desirable to have a simple mechanistic model to simultaneously describe both PK, including TMDD, and RO at the site of action (SoA). In this tutorial, we introduce a physiologically inspired PKRO (piPKRO) model for mAbs targeting membrane receptors. The linear PK part (referred to as the piPK model) is modified from the classical 2-compartment PK model to include using the physiological compartment volumes, adding drug clearance in extravascular compartments, describing mAb concentration in tissues reflecting measured partition coefficients, and target expression and drug binding based on the location of target expression. A few macroparameters including P