Open AccessA Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data
Author(s) -
Jones Hannah M.,
Zhang Zhiwei,
Jasper Paul,
Luo Haobin,
Avery Lindsay B.,
King Lindsay E.,
Neubert Hendrik,
Barton Hugh A.,
Betts Alison M.,
Webster Robert
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12461
Subject(s) - pharmacokinetics , monoclonal antibody , in vitro , in vivo , chemistry , intracellular , antibody , receptor , distribution (mathematics) , pharmacology , microbiology and biotechnology , biology , biochemistry , immunology , mathematical analysis , mathematics
Monoclonal antibody ( mA b) pharmacokinetics ( PK ) have largely been predicted via allometric scaling with little consideration for cross‐species differences in neonatal Fc receptor (FcRn) affinity or clearance/distribution mechanisms. To address this, we developed a mA b physiologically‐based PK model that describes the intracellular trafficking and FcRn recycling of mA bs in a human FcRn transgenic homozygous mouse and human. This model uses mA b‐specific in vitro data together with species‐specific FcRn tissue expression, tissue volume, and blood‐flow physiology to predict mA b in vivo linear PK a priori . The model accurately predicts the terminal half‐life of 90% of the mA bs investigated within a twofold error. The mechanistic nature of this model allows us to not only predict linear PK from in vitro data but also explore the PK and target binding of mA bs engineered to have pH‐ dependent binding to its target or FcRn and could aid in the selection of mA bs with optimal PK and pharmacodynamic properties.