title: Prediction of human clearance based on animal data and molecular properties.
abstract: Human clearance is often predicted prior to clinical study from in vivo preclinical data by virtue of interspecies allometric scaling methods. The aims of this study were to determine the important molecular descriptors for the extrapolation of animal data to human clearance and further to build a model to predict human clearance by combination of animal data and the selected molecular descriptors. These important molecular descriptors selected by genetic algorithm (GA) were from five classes: quantum mechanical, shadow indices, E-state keys, molecular properties, and molecular property counts. Although the data set contained many outliers determined by the conventional Mahmood method, the variation of most outliers was reduced significantly by our final support vector machine (SVM) model. The values of cross-validated correlation coefficient and root-mean-squared error (RMSE) for leave-one-out cross-validation (LOOCV) of the final SVM model were 0.783 and 0.305, respectively. Meanwhile, the reliability and consistency of the final model were also validated by an external test set. In conclusion, the SVM model based on the molecular descriptors selected by GA and animal data achieved better prediction performance than the Mahmood method. This approach can be applied as an improved interspecies allometric scaling method in drug research and development.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Wenkang
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Lv
authors.initials: L
authors.lastname: Geng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Department of Obstetrics and Gynecology, Institute of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Lu
authors.affiliation: Pfizer (China) Research and Development Co., Ltd., Shanghai, 201203, China.
authors.forename: Guangli
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Jianxiu
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Functional Nano & Soft Materials Laboratory (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, 215123, China.
authors.forename: Tingjun
authors.initials: T
authors.lastname: Hou
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Lu
mesh_terms: D000465:Algorithms; D000818:Animals; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010599:Pharmacokinetics; D060388:Support Vector Machine
chemical_list: D004364:Pharmaceutical Preparations
keywords: clearance; interspecies scaling; mathematical model; oral drug delivery; pharmacokinetics; support vector machine