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Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

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Abstract

Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.

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Acknowledgments

We thank Professor Geoff Tucker (Simcyp Limited, A Certara Company, Blades Enterprise Centre, John Street, Sheffield S2 4SU, U.K.) for his thorough review of the manuscript and constructive comments.

Conflict of Interest

Linzhong Li, Iain Gardner, and Masoud Jamei are employees of Simcyp (a Certara company). Miroslav Dostalek was employed at Simcyp (a Certara company) at the time of work on minimal PBPK model. The findings and the conclusions in this report are those of the authors and do not necessarily represents the view of Simcyp (a Certara company) and F. Hoffmann-La Roche AG.

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Authors and Affiliations

  1. Simcyp Limited, A Certara Company, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK

    Linzhong Li, Iain Gardner & Masoud Jamei

  2. F. Hoffmann-La Roche AG, pRED, Pharma Research and Early Development, Non-Clinical Safety, Grenzacherstrasse, Basel, Switzerland

    Miroslav Dostalek

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  1. Linzhong Li
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  2. Iain Gardner
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Correspondence to Linzhong Li.

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Li, L., Gardner, I., Dostalek, M. et al. Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model. AAPS J 16, 1097–1109 (2014). https://doi.org/10.1208/s12248-014-9640-5

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  • DOI: https://doi.org/10.1208/s12248-014-9640-5

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