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Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis
Krippendorff, Ben-Fillippo; Kuester, Katharina; Kloft, Charlotte; Huisinga, Wilhelm
Receptor mediated endocytosis (RME) plays a major role in the disposition of therapeutic protein drugs in the body. It is suspected to be a major source of nonlinear pharmacokinetic behavior observed in clinical pharmacokinetic data. So far, mostly empirical or semi-mechanistic approaches have been used to represent RME. A thorough understanding of the impact of the properties of the drug and of the receptor system on the resulting nonlinear disposition is still missing, as is how to best represent RME in pharmacokinetic models. In this article, we present a detailed mechanistic model of RME that explicitly takes into account receptor binding and trafficking inside the cell and that is used to derive reduced models of RME which retain a mechanistic interpretation. We find that RME can be described by an extended Michaelis–Menten model that accounts for both the distribution and the elimination aspect of RME. If the amount of drug in the receptor system is negligible
Keyword(s): Biology; Hamilton Institute; Chemistry; Recepter mediated endocytosis; Nonlinear pharmacokinetics; Michaelis–Menten; Therapeutic proteins; Biopharmaceuticals; Epidermal growth factor receptor; Nonlinear dispostition; Receptor trafficking; Antibodies; Hamilton Institute.
Publication Date:
2009
Type: Journal article
Peer-Reviewed: Yes
Institution: Maynooth University
Citation(s): Krippendorff, Ben-Fillippo and Kuester, Katharina and Kloft, Charlotte and Huisinga, Wilhelm (2009) Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis. Journal of Pharmacokinetics and Pharmacodynamics , 36 (3). pp. 239-260. ISSN 1567-567X
Publisher(s): Springer Verlag
File Format(s): application/pdf
Related Link(s): http://mural.maynoothuniversity.ie/1658/1/fulltext.pdf
First Indexed: 2020-01-31 06:02:37 Last Updated: 2020-04-02 07:43:56