Investigating the NonclinicalADMEandPK/PDof an Antibody–Drug Conjugate: A Case Study of Ado‐Trastuzumab Emtansine (T‐DM1)

Abstract Antibody‐drug conjugates (ADCs) are a growing class of anticancer agents combining the targeting ability of an antibody with the potency of a cytotoxic agent. Ado‐trastuzumab emtansine (Kadcyla ® , or Trastuzumab‐DM1 (T‐DM1)) is approved for the treatment of human epidermal growth factor receptor 2+ (HER2+) metastatic breast cancer and in development for other HER2+ indications. This chapter explores the pharmacokinetic/pharmacodynamic (PK/PD) and absorption, distribution, metabolism, and excretion (ADME) strategy and data for T‐DM1. In the course of the development of T‐DM1, a substantial body of information was generated describing the ADME characteristics of the ADC. The strategy was to develop a comprehensive understanding of the behavior of T‐DM1, including its PK/PD, distribution, in vivo and ex vivo stability, catabolic fate, and excretion. The foundation upon which PK and ADME evaluation is built is thorough and robust bioanalytical methods capable of determining the presence of key components of the molecule of interest.