An Integrated Transfer Learning and Multitask Learning Approach for Pharmacokinetic Parameter Prediction Zhuyifan Ye1, Yilong Yang1,2, Xiaoshan Li2, Dongsheng Cao3, Defang Ouyang1* 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China 2Department of Computer and Information Science, Faculty of Science and Technology, University of Macau, Macau, China 3Xiangya School of Pharmaceutical Sciences, Central South University, No. 172, Tongzipo Road, Yuelu District, Changsha, People’s Republic of China Note: Zhuyifan Ye and Yilong Yang made equal contribution to the manuscript. Corresponding author: Defang Ouyang, email:
[email protected]; telephone: 853-88224514. ABSTRACT: Background: Pharmacokinetic evaluation is one of the key processes in drug discovery and development. However, current absorption, distribution, metabolism, excretion prediction models still have limited accuracy. Aim: This study aims to construct an integrated transfer learning and multitask learning approach for developing quantitative structure-activity relationship models to predict four human pharmacokinetic parameters. Methods: A pharmacokinetic dataset included 1104 U.S. FDA approved small molecule drugs. The dataset included four human pharmacokinetic parameter subsets (oral bioavailability, plasma protein binding rate, apparent volume of distribution at steady-state and elimination half-life). The pre-trained model was trained on over 30 million bioactivity data. An integrated transfer learning and multitask learning approach was established to enhance the model generalization. Results: The pharmacokinetic dataset was split into three parts (60:20:20) for training, validation and test by the improved Maximum Dissimilarity algorithm with the representative initial set selection algorithm and the weighted distance function. The multitask learning techniques enhanced the model predictive ability.