Abstract 2065: Development of a general framework for effective translation of in vitro synergistic combination into in vivo synergy using a systemic modeling approach.
Authors: Vega-Villa Karina , Ihnat Michael , Woo Sukyung 
Published: August 2014

Purpose: Failure of identifying optimal dosing regimen is often responsible for failed or inconclusive clinical evaluation of combination cancer therapy, and selecting synergistic combination doses remains a great challenge. The information from well-designed in vitro and preclinical animal drug combination studies - which include dose, pharmacokinetics (PK), efficacy, synergism/antagonism, and schedule dependence - can significantly contribute to the success of drug combination clinical trials. However, general methodologies for translating in vitro combination effects into preclinical and clinical in vivo doses are lacking. This study aims to develop a systemic approach for effective in vitro-in vivo translation by the combined efforts of experimental data and computational modeling.

Methods: Erlotinib and CLEFMA, a novel curcuminoid, against erlotinib-resistant NSCLC (H441) was used as a proof-of-concept drug combination for this study. The key components of the framework include a) evaluation of in vitro combination effects of two drugs and estimation of the interaction parameter (ψ) that defines the nature of drug interaction; b) in vivo PK information of two drugs in plasma and tumor that was obtained from the literature and characterized by compartmental PK models; and c) in vivo inhibitory effects of each drug alone on tumor growth in xenograft mice, which were described by a modified Simeoni model. The final integrated model was then used to describe combined in vivo effects by incorporating the interaction parameter, thereby predicting optimal combination doses.

Results: In vitro combined effects of two drugs were fitted to 3-dimensional response surface model and suggested to be synergistic (ψ = 0.68). Erlotinib PK in tumor-bearing mice following oral administration was described using a two-compartment model and CLEFMA PK following intravenous administration was simulated. Plasma-to-tumor distribution ratio was 0.6 for erlotinib and 0.36 for CLEFMA and tumor drug concentrations were used as a driving force for the observed inhibitory effects on tumor growth in vivo to closely mimic in vitro effective concentrations. The tumor progression in non-treated mice was depicted by an exponential growth followed by a linear growth. In treated mice, the combined inhibitory effect was described as a function of the tumor drug concentrations and the interaction parameter ψ.

Conclusion: The present study lays out the strategy and tactics for translating in vitro synergy into maximal in vivo synergy. The developed approach can be used to better design preclinical experiments in xenograft model in a rational manner after in vitro combination studies, and to select the most advantageous in vivo combination doses and schedules for maximal synergy, thereby facilitating early anticancer drug development.

Citation Format: Karina Vega-Villa, Michael Ihnat, Sukyung Woo. Development of a general framework for effective translation of in vitro synergistic combination into in vivo synergy using a systemic modeling approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2013-2065