Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics

Abstract

Therapeutic proteins (TPs) have ranked among the most important and fastest-growing classes of drugs in the clinic, yet the development of successful TPs is often limited by unsatisfactory efficacy.Understanding pharmacokinetic (PK) characteristics of TPs is key to achieving sufficient and prolonged exposure at the site-of-action, which is a prerequisite for eliciting desired pharmacological effects. PK modeling represents a powerful tool to investigate factors governing in vivo disposition of TPs. In this mini-review, we discuss many state-of-the-art models that recapitulate critical processes in each of the absorption, distribution, metabolism/catabolism, and excretion (ADME) pathways of TPs, which can be integrated into the physiologically-based pharmacokinetic (PBPK) framework. Additionally, we provide our perspectives on current opportunities and challenges for evolving the PK models to accelerate the discovery and development of safe and efficacious TPs. Significance statementThis minireview provides an overview of mechanistic PK models developed to characterize ADME properties of therapeutic proteins (TPs), which can be used to support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action are being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolve existing platform PK models to facilitate successful bench-to-bedside translation of these promising drug molecules.

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics

“…Availability of additional data in preclinical settings (such as measurements in the lymph, at the level of the injection site, a wide range of dose levels or use of absorption modifiers) offers opportunities for the development of mechanism-based models. 32 Conversely, clinical PK data are mostly systemic exposures constraining the potential for development of advanced s.c. models for biologics. 33 In these models, the absorption phase is mostly captured with a first-order rate constant, whereas the systemic distribution and elimination phases are captured using target-mediated drug disposition models with or without integration of antidrug antibody kinetics.…”

“…Simple models with a single absorption pathway, a few parameters (such as, an absorption rate constant and bioavailability), and with or without evaluation of covariates are often used in clinical studies. Availability of additional data in preclinical settings (such as measurements in the lymph, at the level of the injection site, a wide range of dose levels or use of absorption modifiers) offers opportunities for the development of mechanism‐based models 32 . Conversely, clinical PK data are mostly systemic exposures constraining the potential for development of advanced s.c. models for biologics 33 .…”

Special Section on Pharmacokinetics and ADME of Biological Therapeutics–Editorial

“…Mathematical and mechanistic PK models are pivotal for describing exposure-efficacy and exposure-toxicity relationships for TPs in preclinical species and humans for diverse scenarios, such as TMDD, FcRn-mediated recycling, renal elimination, and tissue distributions. In addition to the IQ efforts on TP ADME characterization, Liu and Shah (2022) further highlighted the importance of PK modeling as a powerful tool to support model-informed drug development of TPs. Understanding PK characteristics of TPs can help with achieving sufficient and prolonged drug exposure at the site of action.…”