Absorption, Distribution, Metabolism, and Excretion of Therapeutic Proteins: Current Industry Practices and Future Perspectives

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.

Boron Clusters as Enhancers of RNase H Activity in the Smart Strategy of Gene Silencing by Antisense Oligonucleotides

“…Recently, boron clusters and their conjugates with nucleosides were shown to have high binding affinity for plasma proteins under in vitro and in vivo conditions [ 39 ]. This is crucial for the pharmacodynamics of the drugs and pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion (ADME) [ 55 ]. Boron clusters have been shown to interact with cationic peptides and other charged and neutral biomolecules, such as acetylcholine and amino acids, as well as vitamins, antibiotics, neuromuscular blockers, and proteins [ 34 ].…”

A Cross Company Perspective on the Assessment of Therapeutic Protein Biotransformation

“…Examples of therapeutic proteins. Reproduced with permission from (Bolleddula et al, 2022) and (Ball et al, 2022).…”

“…Consequently, biotransformation has not been routinely required as part of the regulatory filings for TPs. In fact, no biotransformation data were included in the US Food and Drug Administration (FDA) submission packages for the majority of TPs approved between 2011 and 2020 (Bolleddula et al, 2022).…”

Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies

“…According to a recent industry-wide survey, the most frequently used routes of administration of therapeutic proteins are intravenous (68%), followed by subcutaneous (23%), and others (e.g., intravitreal and intratumoral, 9%) [1]. Subcutaneous (SC) drug products can be self-administered by a patient or administered by another person at home, which is an advantage over intravenous (IV) administration especially for chronic use.…”