Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations
Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations
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DOI：
10.1124/dmd.114.058099
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发表时间：
2014-09-01
影响因子：
3.9
通讯作者：
Rostami-Hodjegan, Amin
中科院分区：
文献类型：
--
作者：
Abduljalil, Khaled;Cain, Theresa;Rostami-Hodjegan, Amin
药代动力学参数的预测准确性通常使用预测倍数误差来评估，即，在观察值的2倍、3倍或n倍内。然而，已发表的研究不同意哪个折叠误差代表准确的预测。此外，来自一项临床研究的“观察数据”通常被用作体外至体内外推（IVIVE）研究的金标准，尽管数据存在显著的研究间变异性和从各种可用报告中进行的主观选择。本研究分析了来自200多项临床研究的已发表的全身清除率（CL）和稳态分布容积（V-ss）值。这些参数获得了17种不同的药物静脉给药后。对数据进行了分析，重点是使用一项特定临床研究的参数值来判断IVIVE性能的适当性，以及从一项临床研究中获得的CL和Vss值“预测”不同临床研究中获得的相同值（使用预测准确度的n倍标准）的能力。双重标准方法是有趣的，因为它被广泛用于IVIVE预测。分析表明，在某些情况下，双重标准的方法是一个不合理的期望时，观察数据来自小样本量的研究。更合理的方法将允许预测标准包括临床研究信息，如样本量和目标参数的方差。提出了一种方法，允许的“成功”的标准被链接到测量的观测值的变化。
Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (V-ss) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and Vss values obtained from one clinical study to "predict" the same values obtained in a different clinical study using the n-fold criteria for prediction accuracy. The twofold criteria method was of interest because it is widely used in IVIVE predictions. The analysis shows that in some cases the twofold criteria method is an unreasonable expectation when the observed data are obtained from studies with small sample size. A more reasonable approach would allow prediction criteria to include clinical study information such as sample size and the variance of the parameter of interest. A method is proposed that allows the "success" criteria to be linked to the measure of variation in the observed value.