Prediction of Monoclonal Antibodies Pharmacokinetics in Human: Identification of a Reference Neonatal Fc Receptor (FcRn) Binding Affinity Using Physiologically Based Pharmacokinetic (PBPK) Modeling

PBPK & PBBM

Program strategies and efficiencies

ACS Pharmacol. Transl. Sci. 2025 Dec 22. Online ahead of print.

Benamara S, Sjögren E, Gattacceca F, Chenel M, Deslandes A, Nguyen L, Teutonico D

Monoclonal antibodies (mAbs) are a cornerstone of modern medicine, but predicting their pharmacokinetics (PK) for First-in-Human (FIH) trials remains a significant challenge. A recent collaboration between Pharmetheus, Sanofi, and Aix-Marseille Université tackles this issue in biotherapeutic development.

To address this, the team used the Open Systems Pharmacology open-source PBPK platform, PK-Sim, to analyze clinical data from 50 mAbs.

The study identified 1.07 μM as reference Kd FcRn.
When applied to a test set of 15 mAbs, plasma exposure (AUC) was accurately predicted for 80% of the drugs, with a prediction error within the 0.80−1.25-fold range.
For 100% of the test drugs, the predictions remained within a "2-fold" error range.
By using human-derived reference value of Kd FcRn within PBPK framework, this approach aligns with recent initiatives to reduce unnecessary animal testing.

This work offers a standardized method that lets developers generate reliable PK predictions early in development. By using a reference 'Kd FcRn value' the industry can move from the lab to the clinic faster, with greater confidence and less reliance on animal testing.

Authors