Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development

Abstract

Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models. Additionally, we discuss current and potential future applications of PBPK in the drug discovery and development timeline for mAbs, spanning from identification of potential target molecules to prediction of potential drug-drug interactions. Finally, we conclude with a discussion of currently available PBPK models for mAbs that could be implemented in the drug development process.

Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

“…Smaller Vp could be indicative of higher peripheral concentration that may influence efficacy. Further evaluation of VRC01 or similar mAbs for HIV prevention may warrant physiologically based pharmacokinetic (PBPK) modelling to understand PK features at the target tissue-level [37] .…”

Informing Development of Bispecific Antibodies Using Physiologically Based Pharmacokinetic‐Pharmacodynamic Models: Current Capabilities and Future Opportunities

“…During subcutaneous absorption, antibodies are usually well absorbed (bioavailability of 50% to 100%), and this process has been simply described through administration of mAbs to the interstitial space of the skin in published PBPK models, mainly because there is low confidence in parameters as rate of fluid flows from injection site through the lymphatics to the circulation and the expression of FcRn in cells present in the lymphatics and lymph nodes 33 as it is generally accepted that the predominant route of absorption of antibody therapeutics following subcutaneous administration is via the lymphatics. 38 Understanding of determinants of BsAb disposition is crucial for the development of PBPK models.…”

“…The elimination of antibodies is mainly via catabolism following endocytosis and transport to the lysosome, with the binding to FcRn playing a role as a protective pathway from degradation and recycling. In PBPK models, FcRn‐mediated protection of IgG is typically described as occurring within the endosomes of the vascular endothelium and requires data describing FcRn expression and the rate of uptake into endothelial cells 33 . TMDD can happen because of the high‐affinity interaction between antibody and target, and parameters such as target expression, target turnover, and target accessibility are also needed.…”

“…PBPK modeling is an approach that has been used to characterize the in vivo behavior of drugs. A recent review 33 focused on PBPK modeling of monoclonal antibodies (mAbs), highlighting the key PK process and parameters to be considered and suggested potential extension of these PBPK models to predict the behavior of the next generation of antibody therapeutics as BsAbs.…”

Role of Physiologically Based Pharmacokinetic Modeling and Simulation in Enabling Model‐Informed Development of Drugs and Biotherapeutics

“…[33][34][35] As reviewed previously, PBPK models have a central role in informing the rational design/discovery and development of monoclonal antibody therapeutics. 36 Unlike simple monoclonal antibodies that are designed to bind a single antigen, bispecific antibodies engage 2 distinct molecular targets, requiring more extensive "systems" knowledge to construct models that capture sequential binding to the 2 targets and impact biological variability in system parameters for both targets on downstream pharmacology. Gibbs et al present a comprehensive overview of the considerations in developing PBPK-PD models for bispecific antibodies.…”