Abstract 4554A: Simple, efficient, and quantitative approach for determination of synergism, additive effect, and antagonism of drugs in vivo using combination index method: a proposition for clinical protocol design and regulatory synergy claims

Abstract

Abstract Based on the systematic dynamic rate derivations with the mass-action principle and mathematical induction-deduction, the median-effect equation of Chou, and the combination index (CI) equation and their algorithm allow quantitative determination of synergism (CI<1), additive effect (CI=1) and antagonism (CI>1) (Pharmacol Rev 58:621-681, 2006). Based on Google Scholar Citations, the CI simulation has been cited 7,712 times in >800 bio-medical journals as of 10.19.2016. However, most citing papers were with experiments in vitro, relative few in vivo and rarely in clinical trials. This is despite the fact that the CI method equation, algorithm, and the CompuSyn software are the same for in vitro and in vivo, although the practical aspects such as sample size, time and cost, the readiness of the end-point measurement, and the ethical considerations are different. Our recent publication (in Fu J et al. Synergy 3: 15-30, 2016) of two-drug combination (docetaxel and T-607 compound, 1:2) against HCT-116 colon carcinoma xenograft in nude mice has demonstrated very desirable synergy. We now illustrate the experimental and data-analytical details of the experimental planning and design, execution, measurements, for docetaxel and T-Compound combination against MX-1 mammary carcinoma xenograft in nude mice. Treatment Q3Dx4 i.v. starting Day 7, and the tumor sizes and bodyweight changes measured on Days 16, 19, and 22. A total of 50 nude mice were used (each drug and combinations, 3 doses each (n=5) plus a control group of 5). Full spectrum of synergism (CI=0.79 to 0.93) were observed on Days 19 and 22. Automated simulation were carried out for dose-effect curve, ME plot, Fa-CI plot, isobologram, and Fa-DRI (Dose-Reduction Index) plot with CompuSyn software (Free download available upon registration via www.combosyn.com). This simple, efficient, “econo-green” bio-research paves the way for drug combination clinical trial design and regulatory synergy claims. Citation Format: Jianing Fu, Ting-Chao Chou. Simple, efficient, and quantitative approach for determination of synergism, additive effect, and antagonism of drugs in vivo using combination index method: a proposition for clinical protocol design and regulatory synergy claims [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4554A. doi:10.1158/1538-7445.AM2017-4554A