Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies.
Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies.
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DOI：
10.1038/psp.2013.73
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发表时间：
2014-01-29
影响因子：
3.5
通讯作者：
Jamei, M
中科院分区：
文献类型：
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作者：
Li, L;Gardner, I;Rose, R;Jamei, M
药理学靶标从细胞脱落，产生也可以结合治疗性蛋白质的可溶性靶标，这是一种常见现象。在本研究中，使用基于生理学的最小药代动力学模型模拟曲妥珠单抗的药代动力学以及化合物与可溶性（血液和组织间隙中）和膜结合（组织间隙中）形式的人表皮生长因子受体2（HER 2）的同时结合。描述曲妥珠单抗与HER 2结合的参数值主要来自体外数据，并研究了不同HER 2水平的影响、膜结合HER 2与脱落抗原之间的亲和力差异以及缓慢结合动力学。该模型模拟了血浆中可溶性靶标浓度在500 - 1，000 ng/ml之间时药物谷浓度的急剧下降。这与观察到曲妥珠单抗半衰期变化的可溶性靶标的临床浓度范围一致。
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.