Biopharmaceutic and pharmacodynamic modeling of the in vitro antiproliferative effect of new controlled delivery systems of cisplatin

A biopharmaceutic–pharmacodynamic model is proposed to characterize the antiproliferative effect of controlled release formulations of cisplatin in cancer cell culture. In vitro release profiles from PLGA [poly(d,l-lactide-co-glycolide)] systems were described using a model based on the characterization of two drug release processes: diffusion and matrix degradation. Cytotoxicity data available consisting of the number of survival cells after a continuous exposure to free or encapsulated cisplatin were simultaneously modeled under the Gompertz framework incorporating the drug release model.The release model parameters showed that particle size was inversely related to the diffusion rate. The antiproliferative effect was described as a function of drug concentrations and exposure times. Two mechanisms were included: (i) an inhibition of cell proliferation, where cisplatin released from PLGA systems was mainly involved, followed by (ii) stimulation of cell death due to cisplatin activity and mediated by the activation of a signal transduction process. Cell accumulation in G2/M phase of the cell cycle followed by the activation of caspase-3, supported both mechanisms.The selected drug-effect model and its model parameters were independent from the formulation, which makes it a suitable tool to explore in silico, alternative in vitro and in vivo scenarios to optimize these delivery systems.