Abstract

Therapeutics proteins (TPs) comprise a variety of modalities including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared to small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group (WG) was sponsored by the Translational and ADME Sciences Leadership Group (TALG) within the Innovation and Quality (IQ) consortium with objectives to: i) better understand the current practices of ADME data generated for TPs across IQ member companies, ii) learn about their regulatory strategy and interaction experiences, and iii) provide recommendations on best practices for conducting ADME studies. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to FDA was also collated by reviewing regulatory submission packages of TPs approved between 2011-2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in BLAs along with future perspectives and recommendations for conducting ADME studies for internal decision making as well as regulatory submissions for TPs.

Significance Statement This article provides comprehensive assessment of the current practices of absorption, distribution, metabolism, and excretion (ADME) data generated for therapeutic proteins across the Innovation and Quality (IQ) participating companies and the utility of the data in discovery, development, and regulatory submissions. The TP ADME working group (WG) working group also recommends the best practices for conducting ADME studies for internal decision making and regulatory submissions.