Abstract：
A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor patient compliance. To solve this issue, there has been great investment into half-life extension of rapidly eliminated drugs using approaches such as albumin binding, fusion to albumin or Fc, or conjugation to polyethylene glycol. Despite clinical successes of half-life extension products, no clear relationship has been drawn between properties of drugs and the pharmacokinetic parameters of their half-life extended analogues. In this study, non-compartmentally derived pharmacokinetic parameters (half-life, clearance, volume of distribution) were collected for 186 half-life extended drugs and their unmodified parent molecules. Statistical testing and regression analysis was performed to evaluate relationships between pharmacokinetic parameters and a matrix of variables. Multivariate linear regression models were developed for each of the three pharmacokinetic parameters and model predictions were in good agreement with observed data with r2 values for each parameter being: half-life: 0.879, clearance: 0.820, volume of distribution: 0.937. Significant predictors for each parameter included the corresponding pharmacokinetic parameter of the parent drug and descriptors related to molecular weight. This model represents a useful tool for prediction of the potential benefits of half-life extension.
摘要：
开发肽和蛋白质疗法的一个挑战是从体内快速消除，需要频繁给药,这可能导致毒性和/或患者依从性差。为了解决这个问题，使用白蛋白结合等方法，对快速消除的药物的半衰期延长进行了大量投资，融合白蛋白或Fc，或与聚乙二醇缀合。尽管半衰期延长产品在临床上取得了成功，药物的性质与其半衰期延长类似物的药代动力学参数之间没有明确的关系。在这项研究中,非隔室衍生的药代动力学参数(半衰期，间隙,分布体积）收集了186种半衰期延长的药物及其未修饰的母体分子。进行统计测试和回归分析以评估药代动力学参数与变量矩阵之间的关系。为三个药代动力学参数中的每一个建立多变量线性回归模型,并且模型预测与观察到的数据非常吻合,每个参数的r2值为:半衰期:0.879,清除率:0.820,分布体积:0.937。每个参数的重要预测因子包括母体药物的相应药代动力学参数和与分子量相关的描述符。该模型代表了用于预测半衰期延长的潜在益处的有用工具。
