A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data
Monoclonal antibody (mAb) 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 mAb physiologically‐based PK model...
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Online Access: | https://doi.org/10.1002/psp4.12461 |
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doaj-c58bb5351c0144759f98b87e000c61f82020-11-25T03:25:17ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062019-10-0181073874710.1002/psp4.12461A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro DataHannah M. Jones0Zhiwei Zhang1Paul Jasper2Haobin Luo3Lindsay B. Avery4Lindsay E. King5Hendrik Neubert6Hugh A. Barton7Alison M. Betts8Robert Webster9BioMedicine Design Pfizer Worldwide R&D Cambridge Massachusetts USARES Group Inc Needham Massachusetts USARES Group Inc Needham Massachusetts USARES Group Inc Needham Massachusetts USADMPK Sanofi Waltham Massachusetts USABioMedicine Design Pfizer Worldwide R&D Andover Massachusetts USABioMedicine Design Pfizer Worldwide R&D Andover Massachusetts USABioMedicine Design Pfizer Worldwide R&D Groton Connecticut USABioMedicine Design Pfizer Worldwide R&D Cambridge Massachusetts USABioMedicine Design Pfizer Worldwide R&D Cambridge Massachusetts USAMonoclonal antibody (mAb) 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 mAb physiologically‐based PK model that describes the intracellular trafficking and FcRn recycling of mAbs in a human FcRn transgenic homozygous mouse and human. This model uses mAb‐specific in vitro data together with species‐specific FcRn tissue expression, tissue volume, and blood‐flow physiology to predict mAb in vivo linear PK a priori. The model accurately predicts the terminal half‐life of 90% of the mAbs 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 mAbs engineered to have pH‐dependent binding to its target or FcRn and could aid in the selection of mAbs with optimal PK and pharmacodynamic properties.https://doi.org/10.1002/psp4.12461 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hannah M. Jones Zhiwei Zhang Paul Jasper Haobin Luo Lindsay B. Avery Lindsay E. King Hendrik Neubert Hugh A. Barton Alison M. Betts Robert Webster |
spellingShingle |
Hannah M. Jones Zhiwei Zhang Paul Jasper Haobin Luo Lindsay B. Avery Lindsay E. King Hendrik Neubert Hugh A. Barton Alison M. Betts Robert Webster A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data CPT: Pharmacometrics & Systems Pharmacology |
author_facet |
Hannah M. Jones Zhiwei Zhang Paul Jasper Haobin Luo Lindsay B. Avery Lindsay E. King Hendrik Neubert Hugh A. Barton Alison M. Betts Robert Webster |
author_sort |
Hannah M. Jones |
title |
A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data |
title_short |
A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data |
title_full |
A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data |
title_fullStr |
A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data |
title_full_unstemmed |
A Physiologically‐Based Pharmacokinetic Model for the Prediction of Monoclonal Antibody Pharmacokinetics From In Vitro Data |
title_sort |
physiologically‐based pharmacokinetic model for the prediction of monoclonal antibody pharmacokinetics from in vitro data |
publisher |
Wiley |
series |
CPT: Pharmacometrics & Systems Pharmacology |
issn |
2163-8306 |
publishDate |
2019-10-01 |
description |
Monoclonal antibody (mAb) 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 mAb physiologically‐based PK model that describes the intracellular trafficking and FcRn recycling of mAbs in a human FcRn transgenic homozygous mouse and human. This model uses mAb‐specific in vitro data together with species‐specific FcRn tissue expression, tissue volume, and blood‐flow physiology to predict mAb in vivo linear PK a priori. The model accurately predicts the terminal half‐life of 90% of the mAbs 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 mAbs engineered to have pH‐dependent binding to its target or FcRn and could aid in the selection of mAbs with optimal PK and pharmacodynamic properties. |
url |
https://doi.org/10.1002/psp4.12461 |
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