Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides.

Amita Datta-Mannan

doi:10.1124/dmd.119.086488

Abstract

Monoclonal antibodies (mAbs) and peptides are an important class of therapeutic modalities that have brought improved health outcomes in areas with limited therapeutic optionality. Presently, there more than 90 mAb and peptide therapeutics on the United States market, with over 600 more in various clinical stages of development in a broad array of therapeutic areas, including diabetes, autoimmune disorders, oncology, neuroscience, and cardiovascular and infectious diseases. Notwithstanding this potential, there is high clinical rate of attrition, with approximately 10% reaching patients. A major contributor to the failure of the molecules is often times an incomplete or poor understanding of the pharmacokinetics (PK) and disposition profiles leading to limited or diminished efficacy. Increased and thorough characterization efforts directed at disseminating mechanisms influencing the PK and disposition of mAbs and peptides can aid in improving the design for their intended pharmacological activity, and thereby their clinical success. The PK and disposition factors for mAbs and peptides are broadly influenced by target-mediated drug disposition and nontarget-related clearance mechanisms related to the interplay between the relationship of the structure and physiochemical properties of mAbs and peptides with physiologic processes. This review focuses on nontarget-related factors influencing the disposition and PK of mAbs and peptides. Contemporary considerations around the increasing in silico approaches to identify nontarget-related molecule limitations and enhancing the druggability of mAbs and peptides, including parenteral and nonparenteral delivery strategies that are geared toward improving patient experience and compliance, are also discussed.

Highlights

Over the last several decades, there has been a staggering increased investment by the medicinal community in the discovery and development of protein-based drugs or biologics
Predictions of monoclonal antibody (mAb) and peptide human PK from preclinical species is routinely leveraged for the design of human dose selection and frequency
The progress made in understanding this space opens up the potential for increasingly extending into and leveraging in silico approaches for the design and selection of mAbs and peptides with the desired human PK properties prior to the generation of molecules and extensive in vivo preclinical PK studies

Summary

Introduction

Over the last several decades, there has been a staggering increased investment by the medicinal community in the discovery and development of protein-based drugs or biologics. In addition to molecule-centric physiochemical properties, several studies have reported physiologic-based protein interactions with circulating serum albumin and the neonatal Fc receptor (FcRn) as key pillars affecting PK and disposition in mAb and peptide biologics.

Results

Conclusion