A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse.
A minimal physiologically based pharmacokinetic model that predicts anti-PEG IgG-mediated clearance of PEGylated drugs in human and mouse.
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DOI：
10.1016/j.jconrel.2018.06.002
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发表时间：
2018-08-28
期刊：
影响因子：
--
通讯作者：
Lai SK
中科院分区：
文献类型：
--
作者：
McSweeney MD;Wessler T;Price LSL;Ciociola EC;Herity LB;Piscitelli JA;Zamboni WC;Forest MG;Cao Y;Lai SK
特异性结合聚乙二醇（PEG）的循环抗体与某些聚乙二醇化治疗药物的疗效降低和不良反应增加有关，PEG是一种常用于蛋白质和纳米颗粒治疗的聚合物。除了聚乙二醇化药物会急性诱导抗聚乙二醇抗体（APA）产生之外，在多达70%的普通人群中也发现通常较低但可检测到的APA水平。尽管APA具有广泛影响，但APA介导的聚乙二醇化药物清除的动态过程，以及为什么许多患者尽管存在预先存在的APA却仍对聚乙二醇化药物有反应，仍未得到很好的理解。在此，我们开发了一个基于生理学的最简药代动力学（mPBPK）模型，该模型纳入了APA和聚乙二醇化药物的各种特性。我们的mPBPK模型重现了APA介导的培戈洛酶加速血液清除的临床药代动力学数据，以及在小鼠中APA依赖性的聚乙二醇化脂质体消除情况。我们的模型预测，只有当APA浓度大于约500纳克/毫升时，聚乙二醇化药物的长效循环才会受到影响，这为为什么APA对聚乙二醇化治疗的影响在大多数患者中似乎有限提供了定量解释。这个mPBPK模型很容易适用于其他聚乙二醇化药物和颗粒，以预测可能使它们无效的APA的精确水平，为支持各种聚乙二醇化治疗药物的临床前和临床研究的开发和解释提供了一个有力工具。
Circulating antibodies that specifically bind polyethylene glycol (PEG), a polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy and increased adverse reactions to some PEGylated therapeutics. In addition to acute induction of anti-PEG antibodies (APA) by PEGylated drugs, typically low but detectable levels of APA are also found in up to 70% of the general population. Despite the broad implications of APA, the dynamics of APA-mediated clearance of PEGylated drugs, and why many patients continue to respond to PEGylated drugs despite the presence of pre-existing APA, remains not well understood. Here, we developed a minimal physiologically based pharmacokinetic (mPBPK) model that incorporates various properties of APA and PEGylated drugs. Our mPBPK model reproduced clinical PK data of APA-mediated accelerated blood clearance of pegloticase, as well as APA-dependent elimination of PEGyated liposomes in mice. Our model predicts that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations greater than ~500 ng/mL, providing a quantitative explanation to why the effects of APA on PEGylated treatments appear to be limited in most patients. This mPBPK model is readily adaptable to other PEGylated drugs and particles to predict the precise levels of APA that could render them ineffective, providing a powerful tool to support the development and interpretation of preclinical and clinical studies of various PEGylated therapeutics.
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影响因子：
10.8
作者：
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