Comprehensive mechanism-based antibody pharmacokinetic modeling.

ABSTRACT

Pharmacokinetic models of antibody distribution and dynamics are useful for predicting and optimizing therapeutic behavior. Targeted antigens are produced and distributed in various tissues in specific patterns in disease phenotypes. Existing models leave out significant mechanistic detail which would enable an understanding of how to modify therapeutics in an optimal manner to allow appropriate tissue penetration in either a healthy or diseased state. The model presented here incorporates additional complexity such as diffusion through endothelial barriers, differential transcytosis properties, FcRn-mediated recycling, and incorporates these properties in an organ-specific manner. This creates a platform which can be expanded upon to include understanding of the effect of target on therapeutic distribution and clearance, differences in dynamics during a diseased versus healthy state, differential dose strategies, and mechanistic translation between animal models and human disease state. This model represents a superior alternative to typical and potentially over-simplified scaling strategies utilized in most existing physiologically-based pharmacokinetic models. Ultimately, this will enable better therapeutic design and greater pharmacological effects.