TY - JOUR T1 - Predicting anti-tumor effect of deoxypodophyllotoxin in NCI-H460 tumor-bearing mice based on in vitro pharmacodynamics and physiologically based pharmacokinetic-pharmacodynamic model JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.079830 SP - dmd.117.079830 AU - Yang Chen AU - Kaijing Zhao AU - Fei Liu AU - Ying Li AU - Zeyu Zhong AU - Shijin Hong AU - Xiaodong Liu AU - Li Liu Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/04/04/dmd.117.079830.abstract N2 - Anti-tumor evaluation in tumor-bearing mouse is time- and energy-consuming. We aimed to investigate whether in vivo anti-tumor efficacy could be predicted based on in vitro pharmacodynamics using deoxypodophyllotoxin (DPT), a developing anti-tumor candidate, as a model compound. Proliferation kinetics of monolayer cultivated NCI-H460 cells under various DPT concentrations was quantitatively investigated accompanied by calibration curves. Koch's two-phase natural growth model combined with sigmoid Emax model, i.e. dM/dt=2λ0λ1M/(λ1+2λ0M)-EmaxCγ/(EC50γ+Cγ)·M, was introduced to describe cell proliferation (M) against time under DPT treatment (C). Estimated in vitro pharmacodynamic parameters were: EC50, 8.97 nM; Emax, 0.820 day-1 and γ, 7.13. A physiologically based pharmacokinetic (PBPK) model including tumor compartment was introduced, which could predict DPT disposition in plasma, tumor tissue and main normal tissues of NCI-H460 tumor-bearing mice following single dose. In vivo pharmacodynamic model and parameters were assumed the same as in vitro ones, and linked with simulated tumor pharmacokinetic profiles by PBPK model, to build a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model. After estimating natural growth parameters (λ0 and λ1), we desirably predicted the tumor growth in NCI-H460 tumor-bearing mice during multi-dose DPT treatment, both in this study and literature, by the PBPK-PD model. The model was further successfully applied to predict tumor growth in SGC-7901 tumor-bearing mice. These data indicated that in vivo anti-tumor efficacy might be predicted based on in vitro cytotoxic assays via PBPK-PD model approach. The approach was demonstrated reasonable and applicable, which might facilitate and accelerate anti-cancer candidate screening and dose regimen design in drug discovery process. ER -