Mahmood Iftekhar
Division of Clinical Evaluation and Pharmacology/Toxicology Branch, Office of Tissues & Advance Therapies (OTAT), Center for Biologic Evaluation and Research, Food & Drug Administration, Silver Spring, MD 20993-0002, United States.
Curr Drug Metab. 2018;19(2):155-164. doi: 10.2174/1389200219666171129114337.
In Physiologically Based Pharmacokinetic (PBPK) models, the most important input parameter is tissue-to-plasma partition coefficient (Kp). Over the years, several empirical methods have been developed to predict Kp in animals.
The objective of this study was to propose two allometric methods to predict Kp from experimentally determined in vivo volume of distribution at steady state (Vss).
In one method, Vss was allometrically predicted (using a fixed exponent 1.0 or 0.8) in a given tissue of the rat and then Kp was predicted for that tissue. In another method, an allometric plot (Kp versus Vss) was developed to predict Kp in a tissue of the rat. In total, Kp values were predicted for 46 drugs and 338 tissues. The predicted Kp values by the proposed two methods were compared with the experimentally determined Kp values as well as empirically predicted Kp values by other investigators.
Comparison of the predicted Kp values by the two proposed methods with experimentally determined Kp values indicated that 67-72% of the predicted Kp values were within two-fold prediction error. The predictive power or accuracy of method 1 (when taken all tissues and all classes of drugs into account) was 19%, 35%, 14%, 35%, 14%, and 13% better than the methods proposed by Arundel, Berezhkovskiy, Jansson et al., Poulin et al., Poulin- Theil, and Rodgers et al. respectively.
The proposed two allometric methods are slightly more accurate than other empirical methods in their predictive performance for the prediction of tissue Kp values for acidic, weak bases and neutral drugs.
在基于生理的药代动力学（PBPK）模型中，最重要的输入参数是组织与血浆的分配系数（Kp）。多年来，已经开发了几种经验方法来预测动物体内的Kp。
本研究的目的是提出两种异速生长方法，根据实验测定的稳态体内分布容积（Vss）预测Kp。
一种方法是在大鼠的特定组织中对Vss进行异速生长预测（使用固定指数1.0或0.8），然后预测该组织的Kp。另一种方法是绘制异速生长图（Kp对Vss）来预测大鼠组织中的Kp。总共对46种药物和338个组织的Kp值进行了预测。将所提出的两种方法预测的Kp值与实验测定的Kp值以及其他研究者通过经验预测的Kp值进行比较。
将所提出的两种方法预测的Kp值与实验测定的Kp值进行比较，结果表明67%-72%的预测Kp值在两倍预测误差范围内。方法1（考虑所有组织和所有类别的药物时）的预测能力或准确性分别比Arundel、Berezhkovskiy、Jansson等人、Poulin等人、Poulin-Theil以及Rodgers等人提出的方法高19%、35%、14%、35%、14%和13%。
所提出的两种异速生长方法在预测酸性、弱碱性和中性药物的组织Kp值方面，其预测性能比其他经验方法略准确。
