Journal
DRUG METABOLISM AND DISPOSITION
Volume 46, Issue 6, Pages 897-907Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.117.079830
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Funding
- National Natural Science Foundation of China [81673505, 81573490]
- Natural Science Foundation of Jiangsu Province of China [BK20161457]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Policy Directive Program of Jiangsu Province [BY2015072-03]
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Antitumor evaluation in tumor-bearing mouse is time-and energy-consuming. We aimed to investigate whether in vivo antitumor efficacy could be predicted on the basis of in vitro pharmacodynamics using deoxypodophyllotoxin (DPT), an antitumor candidate in development, as a model compound. Proliferation kinetics of monolayer-cultivated NCI-H460 cells under various DPT concentrations were quantitatively investigated and expressed as calibration curves. Koch two-phase natural growth model combined with sigmoid E-max model, i.e., dM/dt = 2 lambda(0)lambda M-1/(lambda(1) + 2 lambda M-0) - EmaxC gamma/(EC50 gamma + C-gamma).M, was introduced to describe cell proliferation (M) against time under DPT treatment (C). Estimated in vitro pharmacodynamic parameters were: EC50, 8.97 nM; E-max, 0.820 day(-1), and gamma, 7.13. A physiologically based pharmacokinetic model including tumor compartment was introduced to predict DPT disposition in plasma, tumor tissue, and main normal tissues of NCI-H460 tumor-bearing mice following a single dose. The in vivo pharmacodynamic model and parameters were assumed the same as the in vitro ones, and linked with simulated tumor pharmacokinetic profiles by a physiologically based pharmacokinetic (PBPK) model to build a PBPK-pharmacodynamic (PBPK-PD) model. After natural growth parameters (lambda(0) and lambda(1)) were estimated, the objective in this study was to predict with the PBPK-PD model the tumor growth in NCI-H460 tumor-bearing mice during multidose DPT treatment, a use of the model similar to what others have reported. In our work, the model was successfully applied to predict tumor growth in SGC-7901 tumor-bearing mice. The resulting data indicated that in vivo antitumor efficacy might be predicted on the basis of in vitro cytotoxic assays via a PBPK-PD model approach. We demonstrated that the approach is reasonable and applicable and may facilitate and accelerate anticancer candidate screening and dose regimen design in the drug discovery process.
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