Biopharmaceutic and pharmacodynamic characterization of the in vitro anti-proliferative effect of new delivery systems of Cisplatin
MarÝa J Garrido1, Helena Colom2, Juan Espinola1, Daniel Moreno1, Sara Zalba1, Conchita Tros1, I˝aki F. Trocˇniz1
: 1, Pharmacy and Pharmaceutical Technology, University of Navarra; Pamplona; 2, Pharmacy and Pharmaceutical Technology, University of Barcelona. Spain.
Background: Despite cisplatin has been used for more than two decades in the treatment of cancer, resistance development and side effects represent serious limitations that are still not solved. New cisplatin controlled delivery systems (CDS) have shown a significant improvement of its therapeutic index, although their characterization has been in general very empirical.
Aim: To characterize the in vitro antiproliferative effect of new cisplatin CDS by a semi-mechanistic biopharmaceutic/pharmacodynamic model, on colon cancer cell lines.
Methods: In vitro release profiles obtained during thirty five days for each of the new CDS [PLGA; poly(D, L-Lactide-co-glycolide)] microparticles of 9 Ám ě (MP), and nanoparticles of 200 and 500 nm ě, respectively (NPs)] were described using the empirical model proposed by Duvvuri et al (2006), characterizing drug-diffusion and drug-release for degradation of the polymeric matrix. All Cytotoxicity data available consisting on the number of survival cells after a continuous exposure from 0 to 144 hours at five different concentrations of free or encapsulated cisplatin were modelled simultaneously using the Gomperzt framework incorporating the drug release model selected previously. All the analyses were performed using the population approach with NONMEM version VI.
Results: The rate of drug-release during the diffusion process associated with a shorter time duration to release the 50% of entrapped drug was greater for the smallest particles. Two mechanisms of drug action could be quantitatively identified, the first inhibiting the rate of cell proliferation and the second eliciting an irreversible cell lost through the activation of an apoptotic signalling pathway.
Conclusion: The drug-effect model selected and its model parameter estimates were independent from the types of CDS, supporting its semi-mechanistic properties, and making it a suitable tool to explore in silico, alternative in vitro and in vivo scenarios to continue research in optimizing the controlled delivery of cisplatin.
 Moreno et al. Eur J Pharm Biopharm 68 :503-12 (2008).
 Duvvuri S et al. Pharm Res 23: 215-23 (2006).