Abstract 5510: Mass-action law based general pharmacodynamics theory and algorithm for quantitative computer simulation of drug-evaluations in cells, in animals and in clinical trials

Abstract

Abstract The Median-Effect Equation (MEE) for single drug, and the Combination Index Equation (CIE) for multiple drug combinations, are basis for general Pharmacodynamics (PD), and Biodynamics (BD). Both, MEE and CIE are derived from system analysis of the Mass-Action Law (MAL). The MAL-PD/BD theory, equations and algorithms allow automated computer simulations for diagnostic plots and quantitative, digital/indexed conclusions. To date, the MAL dynamic theory is cited over 15,000 times, in over 1,248 biomedical journals. The publications include studies in vitro, in cell, in animal and in clinical trial levels, as indicated in Google Scholar Citations -Ting-Chao Chou, or in Pharmacol. Rev. 58: 621-681, 2006 (cited 3,119 times in 914 journals). MEE indicates dose and effect are interchangeable, and all PD Dose-Effect curves (DEC) can be linearized by the Median-Effect Plot (MEP), x= Log (dose) vs y= Log {(fraction affected (fa)/(fraction unaffected (fu)}, where fa+fu=1, and when fa=fu, gives the Median-Effect Dose (Dm). The slope gives “m” value (dynamic order, signifying the shape of DEC), and the Antilog of x-intercept gives the “Dm” value, (signifying the potency of half-affected, such as IC50, ED50, or LD50). The MEE, is the unified theory of the Michaelis-Menten Eq. for enzyme half-saturation, Handerson-Hasselbalch Eq. for pH half-ionization, Hill Eq. for ligand half-occupancy, and the Scatchard Eq, for receptor half-bond and half-free. Since MEP linearizes the DEC, it requires only a minimum of two data pints to simulate entire DEC. Thus, the Two-Data-Point Theory is extremely cost-effective for animal studies and clinical trial protocol designs, as only small number data points is required to achieve efficient computer simulations, with digital/index conclusions. In CIE, CI<1, =1, and >1, quantitatively defines Synergism, Additive Effect, and Antagonism, respectively, for 2 to n drug combs, using CompuSyn. PD requires multiple doses (3-4 doses in animals; 2-3 doses in clinical trials) since single dose yields a data Point, but “a point” which has “no shape”, thus, it is Not a PD in Vivo. For 2-drug-combos using the CI method in vivo for drug A, B, and A+B, require only 10 data points, (3+3+3 plus one control). Earlier examples with CI method in vivo are: 1. Anti-HIV Combos (AZT+IFN, using only 36 AIDS patients), and 2. Anti-cancer Combos (Taxotere+T607, against HCT-116 colon carcinoma xenograft in nude mice), both used only 10 data points and both achieved quantitative determination of Synergism. This report reaffirm Example 2 with the same drug combos against MX-1 mammary carcinoma xenograft in nude mice, using only 10 data points, showed similar synergy at ED75 to ED97, CI= 0.82-0.79 for MX-1, and CI= 0.98-0.64 for HCT-116. Citation Format: Ting-Chao Chou. Mass-action law based general pharmacodynamics theory and algorithm for quantitative computer simulation of drug-evaluations in cells, in animals and in clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5510.