Maiara Cássia Pigatto (1, 2, 3) Renatha Menti Roman (2) Letizia Carrara (3) Paolo Magni (3) and Teresa Dalla Costa (1, 2)
(1) Pharmaceutical Sciences Graduate Program, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (2) Centro BioanalÃtico de Medicamentos, College of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, Brazil (3) Dipartimento di Ingegneria Industriale e dell'Informazione, University of Pavia, Italy
Objectives: Describing the in vitro and in vivo anticancer effect of etoposide by a PK/PD model. Comparison of the in vitro and in vivo PK/PD parameters.
Methods: In vitro antitumor activity was determined against Walker-256 (W256) carcinosarcoma cells exposed to different constant concentrations and to dynamic concentration-time profiles that mimic the concentrations in vivo experiments. In in vivo tumor growth inhibition experiments, W256 tumor-bearing Wistar rats received etoposide 5 or 10 mg/kg i.v. bolus every day for 8 and 4 days, respectively. Tumor volume was monitored daily during and after drug treatment. The protocol of the in vivo studies was approved by UFRGS Ethics Committee on Animal Use (#22302). Data were analyzed starting from the Del Bene [1] and Simeoni [2] TGI models (http://repository.ddmore.eu). An Emax function was introduced both in vitro and in vivo in the PD model to take into account nonlinearity in the k2 (drug potency) parameter. A three-compartment popPK model was developed in a separate group of animals. Moreover, the drug concentration profile in tumor simultaneously measured with plasma data was also linked to the effect. PK/PD analysis was conducted using Monolix v.4.3.3, on average data for in vitro study and by mean of a nonlinear mixed-effect model for in vivo data.
Results: The nonlinear mixed-effect model was capable to describe the sources of between-subject variability in the in vivo tumor growth. In the in vitro experiments, the model estimated on data from constant exposure well predicted the antitumor activity from the dynamic concentration-time profile experiments. The comparison between in vivo and in vitro PK/PD parameters showed an increased etoposide anticancer activity in vivo than in vitro.
Conclusions: The same TGI model can successfully predict the etoposide effect after in vivo and in vitro exposure. In the in vitro approach, the antitumor effect following dynamic concentrations can be simulated using the parameters estimates from constant exposures, without the need of time-consuming experiments.
Acknowledgments: Financial support from CNPq/Brazil and doctorate scholarship from CAPES/Brazil.
References:
[1] Del Bene F, Germani M, De Nicolao G, Magni P, Re CE, Ballinari D, Rocchetti M. A model-based approach to the in vitro evaluation of anticancer activity. Cancer Chemother Pharmacol (2009) 63 (5):827– 36.
[2] Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M, Poggesi I and Rocchetti M. Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administrations of anticancer agents. Cancer Res (2004) 64: 1094-1101.
Reference: PAGE 24 (2015) Abstr 3407 [www.page-meeting.org/?abstract=3407]
Poster: Drug/Disease modeling - Oncology