Application of physiologically-based pharmacokinetic models for therapeutic proteins and other novel modalities.

Abstract

The past two decades have seen diversification of drug development pipelines and approvals from traditional small molecule therapies to alternative modalities including monoclonal antibodies, engineered proteins, antibody drug conjugates (ADCs), oligonucleotides and gene therapies. At the same time, physiologically-based pharmacokinetic (PBPK) models for small molecules have seen increased industry and regulatory acceptance. This review focusses on the current status of the application of PBPK models to these newer modalities and give a perspective on the successes, challenges and future directions of this field. There is greatest experience in the development of PBPK models for therapeutic proteins, and PBPK models for ADCs benefit from prior experience for both therapeutic proteins and small molecules. For other modalities, the application of PBPK models is in its infancy. Challenges are discussed and a common theme is lack of availability of physiological and experimental data to characterise systems and drug parameters to enable a priori prediction of pharmacokinetics. Furthermore, sufficient clinical data are required to build confidence in developed models. The PBPK modelling approach provides a quantitative framework for integrating knowledge and data from multiple sources and can be built on as more data becomes available.