Quantitative Pharmacology and Individualized Therapy Strategies in Development of Therapeutic Proteins for Immune-Mediated Inflammatory Diseases
by Honghui Zhou, Diane R. Mould
7Modeling Approaches to Characterize Target‐Mediated Pharmacokinetics and Pharmacodynamics for Therapeutic Proteins
Leonid Gibiansky and Ekaterina Gibiansky
QuantPharm LLC, North Potomac, MD, USA
7.1 Introduction
Many therapeutic proteins are designed to be highly specific and act by binding to a specific target. Binding to the target may strongly influence or even dominate pharmacokinetic (PK) and pharmacodynamic (PD) properties of these drugs, especially at low concentrations. Therapeutic proteins are cleared by two distinct pathways: linear (non‐target) and target mediated. Catabolism (for large molecules, e.g. whole immunoglobulin G (IgG) antibodies) and renal filtration (for smaller molecules, e.g. antibody fragments) are mostly responsible for the linear clearance. These mechanisms are more important at high concentrations when the nonlinear target‐mediated elimination pathway is saturated. Target‐mediated clearance eliminates drug–target complex that is created by binding of the drug to its target. This clearance mechanism commonly involves internalization of cell surface receptors (if the target is on a cell surface) followed by endocytosis, or catabolism (for soluble targets). Target‐mediated clearance may dominate elimination at low concentrations, resulting in faster than linear clearance of the drug.
The term “target‐mediated drug disposition” (TMDD) was first introduced by Levy [1]. A TMDD model, that is, a mathematical description of the TMDD processes, has been proposed ...