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Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models
- The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.…
Author details: | Ludivine Fronton, Sabine Pilari, Wilhelm HuisingaORCiDGND |
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DOI: | https://doi.org/10.1007/s10928-014-9349-1 |
ISSN: | 1567-567X |
ISSN: | 1573-8744 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/24493102 |
Title of parent work (English): | Journal of pharmacokinetics and pharmacodynamics |
Publisher: | Springer |
Place of publishing: | New York |
Publication type: | Article |
Language: | English |
Year of first publication: | 2014 |
Publication year: | 2014 |
Release date: | 2017/03/27 |
Tag: | Classical compartment model; Extravasation rate-limited tissue model; PBPK; mAb disposition |
Volume: | 41 |
Issue: | 2 |
Number of pages: | 21 |
First page: | 87 |
Last Page: | 107 |
Funding institution: | Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modeling; Freie Universitat Berlin; Universitat Potsdam, Germany |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |