Development of a Subcellular Semimechanism-Based Pharmacokinetic/Pharmacodynamic Model to Characterize Paclitaxel Effects Delivered by Polymeric Micelles

Abstract

A transit compartment model was widely and successfully applied to characterize the complex time course of cancer chemotherapeutic effects in vivo or in vitro. However, the underlying mechanisms were not quantitatively depicted. This study aimed to develop a semimechanism-based cellular pharmacokinetic/pharmacodynamic (PK/PD) model to characterize paclitaxel (PTX) effect delivered by PLGA-PEG micelles which was based on analysis of drug subcellular distribution, the tubulin assembly level, the cell cycle shift, and the resulting cytotoxicity. Human breast cancer cell line MCF-7 was exposed to PTX at the concentration of 20 and 40 ng/mL. The in vitro pharmacokinetics of micelle-entrapped PTX was described by a 3-compartment model composed of membrane/organelle, nucleus, and cytoskeleton. A hypothetical effect compartment was used to characterize the distribution delay. The time course of tubulin polymerization stimulation was fitted by the indirect response model. The relationship between tubulin polymerization and G2/M cell population was described by a linear model, and the promoting effect of G2/M arrest on the cytotoxicity was characterized by the Emax model. The proposed model captured the data successfully and described the cellular mechanism of antimitotic drug nanoparticles quantitatively. The methodology and the resulting model could be a supplement for traditional in vivo studies.