A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics

Krutika Patidar; Nikhil Pillai; Saroj Dhakal; Lindsay B Avery; Panteleimon D Mavroudis

doi:10.1007/s10928-023-09899-z

A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics

J Pharmacokinet Pharmacodyn. 2024 Feb 24. doi: 10.1007/s10928-023-09899-z. Online ahead of print.

Authors

Krutika Patidar¹, Nikhil Pillai², Saroj Dhakal², Lindsay B Avery³, Panteleimon D Mavroudis⁴

Affiliations

¹ Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY, USA.
² Global DMPK Modeling & Simulation, Sanofi, 350 Water St, Cambridge, MA, 02141, USA.
³ Global DMPK Innovation, Sanofi, Cambridge, MA, USA.
⁴ Global DMPK Modeling & Simulation, Sanofi, 350 Water St, Cambridge, MA, 02141, USA. panteleimon.mavroudis@sanofi.com.

PMID: 38400996
DOI: 10.1007/s10928-023-09899-z

Abstract

Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties. The model's compound-specific input includes molecular weight, molecular size (Stoke's radius), molecular charge, binding affinity to FcRn, and specific antigen affinity. Through derived and fitted empirical relationships, the model demonstrates the effect of these compound-specific properties on antibody disposition in both plasma and peripheral tissues using observed PK data in mice and humans. The mPBPK model applies the two-pore hypothesis to predict size-based clearance and exposure of full-length antibodies (150 kDa) and antibody fragments (50-100 kDa) within a onefold error. We quantitatively relate antibody charge and PK parameters like uptake rate, non-specific binding affinity, and volume of distribution to capture the relatively faster clearance of positively charged mAb as compared to negatively charged mAb. The model predicts the terminal plasma clearance of slightly positively and negatively charged antibody in humans within a onefold error. The mPBPK model presented in this work can be used to predict the target-mediated disposition of a drug when compound-specific and target-specific properties are known. To our knowledge, a combined effect of antibody weight, size, charge, FcRn, and antigen has not been incorporated and studied in a single mPBPK model previously. By conclusively incorporating and relating a multitude of protein's physicochemical properties to observed PK, our mPBPK model aims to contribute as a platform approach in the early stages of drug development where many of these properties can be optimized to improve a molecule's PK and ultimately its efficacy.

Keywords: Minimal PBPK; Monoclonal antibody; PBPK; Size-based transport; Tissue disposition; Two-pore model.