Abstract 5467: Application of modeling and simulation to the development of MBLI87, a new BCRP inhibitor

Abstract

Abstract Objectives: Breast Cancer Resistance Protein (BCRP) confers resistance to irinotecan (CPT11) and its active metabolite SN38. MBLI87, a new specific and non-toxic BCRP inhibitor, has proven its efficacy to reverse CPT11 BCRP-mediated resistance in xenografts. The present work aimed at: 1) Optimizing CPT11+MBLI87 combination in mice through a model-based approach; 2) Comparing MBLI87 activity with that of gefitinib, the BCRP reference inhibitor, when combined to CPT11; 3) Assessing how modeling and simulation can be applied to early drug development. Methods: Mice were xenografted with HEK-293 cells expressing BCRP. Based on very preliminary data from these xenografted mice treated with 2 chemotherapy cycles (CPT11 +/- MBLI87, gefitinib) during 8 weeks including a 2-week rest period, we developed a Non Linear Mixed Effects (NLME) tumor growth inhibition model. Because only a few numbers of individuals were in each treatment group, NLME model was used to analyze the data. This method uses information from the entire experiment to estimate model parameters, allowing the analysis of sparse data. We used a modified Simeoni et al. model: a Kinetic-PharmacoDynamic (K-PD) component was introduced to deal with the lack of pharmacokinetic data (a drug accumulation and a mono-exponential elimination were assumed according to the dosing schedule) and a pharmacodynamic interaction between CPT11 and MBLI87/gefitinib was considered. Simulations, based on the NLME model and parameter estimates, were conducted to find the optimized dosing regimen able to maximize CPT11+MBLI87 combination effect. A confirmatory study was then carried out on xenografted mice to assess the validity of this optimized regimen. Results: This analysis showed that MBLI87 had no cytotoxic effect when administered alone (potency = 10−2 mg.d−1). A synergistic effect was found between CPT11 and MBLI87 whereas none was found with gefitinib (5.5 vs 0.1 mg−1). Simulations predicted that maximal tumor growth inhibition was reached for CPT11 given 3 days a week at 30 mg.kg−1 and MBLI87 given 5 days a week at 2.4 mg.kg−1 with no rest period. In the confirmatory study, tumor growth rates and drug potency estimates were similar to those from the former study. The interaction parameter was less than previously estimated suggesting that MBLI87 could be more active if administered on an intermittent basis with rest periods. Conclusions: NLME approach allowed describing tumor growth dynamics, quantify MLBI87 action and generate new hypotheses on MBLI87 action to anticipate the next steps of its development. MBLI87 was able to reverse CPT11 BCRP-mediated resistance at a 20-fold lower dose than gefitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5467. doi:10.1158/1538-7445.AM2011-5467