期刊
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
卷 3, 期 1, 页码 -出版社
WILEY
DOI: 10.1038/psp.2013.73
关键词
-
资金
- Simcyp Limited (UK) (a Certara Company)
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.
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