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Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies.


ABSTRACT: Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000?ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e96; doi:10.1038/psp.2013.73; published online 29 January 2014.

SUBMITTER: Li L 

PROVIDER: S-EPMC3910015 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies.

Li L L   Gardner I I   Rose R R   Jamei M M  

CPT: pharmacometrics & systems pharmacology 20140129


Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter value  ...[more]

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