title: Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human.
abstract: Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based onin vitroandin silicoinputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed thatKt:pl,u(unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated byin vivodata of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Kaijing
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Miao
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center of Pharmacokinetics and Metabolism, College of Pharmacy, China Pharmaceutical University Nanjing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
keywords: deoxypodophyllotoxin; interspecies allometric scaling; physiologically based pharmacokinetic model; unbound fraction in plasma; unbound tissue-to-plasma concentration ratio