Drug ratio–dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo

Abstract

Irinotecan and cisplatin are two established anticancer drugs, which together constitute an effective combination for treating small-cell lung cancer. We investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vivo administration. Irinotecan and cisplatin combinations were evaluated systematically for drug ratio-dependent synergy in vitro using a panel of 20 tumor cell lines. In vitro screening informatics on drug ratio-dependent cytotoxicity identified a consistently antagonistic region between irinotecan/cisplatin molar ratios of 1:2 to 4:1, which was bordered by two synergistic regions. Liposomal co-formulations of these two agents were developed that exhibited plasma drug half-lives of 6 hours and maintained a fixed drug ratio for more than 24 hours. Drug ratio-dependent antitumor activity was shown in vivo for these liposome formulations, and irinotecan/cisplatin ratios between 5:1 and 10:1 were identified as therapeutically optimal. The relationship between irinotecan/cisplatin ratio and in vivo efficacy was consistent with in vitro drug ratio dependency results. Superior antitumor activity was observed for the liposome-encapsulated 7:1 molar ratio of irinotecan/cisplatin (designated CPX-571) compared with the free-drug cocktail in all models tested. Further efficacy studies in a range of human tumor xenografts, including an irinotecanresistant model, showed that both liposomal agents contributed to the overall efficacy in a manner consistent with in vivo synergy. These results show the ability of drug delivery technology to enhance the therapeutic activity of irinotecan/cisplatin combination treatment by maintaining synergistic ratios in vivo. CPX-571, a fixed-ratio formulation of irinotecan and cisplatin, is a promising candidate for clinical development.

Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy in non-small-cell lung cancer

“…As different ratios of drug combinations may create different effects (synergistic, additive, or antagonistic), fixing ratios to achieve the best cytotoxicity effect and greatest synergy makes sense. 20 However, the traditional combination drug delivery system, namely the drug cocktail, is limited by the inconsistent biodistribution and pharmacokinetics of drugs and is extremely challenging for treatment optimization. 21 In order to solve these issues, the present study explored a new approach by covalently conjugating the two drugs at different molar ratios on a macromolecule through hydrolyzable linkers.…”

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

“…The acquisition of drug resistance by multiple myeloma cells often requires that a combination of two or more drugs be prescribed to effectively promote cell death by synergistically disrupting different cellular mechanisms necessary for growth and survival (1). Although two drugs can demonstrate synergy, they are usually only synergistic, or exhibit the greatest synergy, at specific drug-to-drug molar ratios (2)(3)(4). Although the two drugs may be administered at the optimal drug ratio for synergy, this does not ensure that this ratio will be maintained at the tumor site due to differences in injection schedules, pharmacokinetic properties, metabolism, and nonuniform biodistribution (5)(6)(7).…”

Improving combination cancer therapy: the CombiPlex ® development platform

“…As described in the following section, results from multiple clinical trials have demonstrated that the CombiPlex platform is able to translate the identification of a synergistic drug ratio in a preclinical setting to the development of combination regimens with improved clinical efficacy [4,[21][22][23].…”