Overview of ADME and PK/PD of ADCs

Abstract

This chapter primarily discusses the absorption, distribution, metabolism/catabolism, and elimination (ADME) properties for antibody‐drug conjugates (ADCs) in oncology therapy and associated pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) modeling of ADCs. Drug‐linker stability is a key attribute required for the development of a successful ADC and has been a primary focus in ADC technology. Premature release of the conjugated drug prior to reaching its intended target may cause unwanted systemic toxicity and reduce the amount of drug delivered to the target tissues. An exposure‐response relationship exists for all therapeutic proteins and small molecule drugs. Multiple modeling efforts have been attempted to incorporate the deconjugation process and/or nonlinear clearance in ADC PK models. A full mechanistic PK model encompassing all major processes of ADC distribution, binding, and elimination of different drug‐to‐antibody ratio (DAR) species was proposed and multiple approximations were applied to simplify the model based on different assumptions.