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 on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data 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.

Predicting Antitumor Effect of Deoxypodophyllotoxin in NCI-H460 Tumor-Bearing Mice on the Basis of In Vitro Pharmacodynamics and a Physiologically Based Pharmacokinetic-Pharmacodynamic Model

“…The developed PBPK model successfully predicted plasma pharmacokinetics of DPT in mice, rats, monkeys, and dogs. Good predictions were also found for pharmacokinetics in tissues of mice (Chen et al, 2016). It is possible to gain a profound understanding of the dynamics of drug disposition in both plasma and tissues/organs through the PBPK model.…”

“…Our previous studies have shown the metabolic kinetics of DPT in hepatic microsomes and its high plasma protein binding in various species (Chen et al, 2016;Xie et al, 2016). Demethylenated metabolite (M2) was shown to be the main metabolite of DPT (Chen et al, 2016;Xie et al, 2016). Subsequently, a whole-body physiologically based pharmacokinetic (PBPK) model of DPT including main organs of body was established on the basis of in vitro assays (Chen et al, 2016).…”

“…Demethylenated metabolite (M2) was shown to be the main metabolite of DPT (Chen et al, 2016;Xie et al, 2016). Subsequently, a whole-body physiologically based pharmacokinetic (PBPK) model of DPT including main organs of body was established on the basis of in vitro assays (Chen et al, 2016). The developed PBPK model successfully predicted plasma pharmacokinetics of DPT in mice, rats, monkeys, and dogs.…”

A Promising Microtubule Inhibitor Deoxypodophyllotoxin Exhibits Better Efficacy to Multidrug-Resistant Breast Cancer than Paclitaxel via Avoiding Efflux Transport

“…DPT (purity > 99%) and DPT-HP-β-CD (content: 2.8%) were kindly provided by the Medicinal and Chemical Institute, China Pharmaceutical University (Chen et al, 2016). Paclitaxel (injection) was purchased from the Yangtze River Pharmaceutical Group (Jiangsu, China).…”

“…As the promising microtubule inhibitor, DPT and its intravenous formulation of β-cyclodextrin inclusion complex (Zhu et al, 2010) have been adopted for phase I evaluation. A physiologically based pharmacokinetics model was also established for better efficacy and safety assessment (Chen et al, 2016). Previous studies have demonstrated that DPT exerts an anti-tumor effect on the human BC MDA-MB-231 cell line in vivo and in vitro (Benzina et al, 2015;Khaled et al, 2016).…”