Abstract CT155: General pharmacodynamics algorithm-based clinical protocol design with two to three dose-data points for single-drug, and ten data points for two-drug-combination synergy quantification, using computer simulation for digitalized data analysis and conclusions

The mass-action law (MAL) based Median-Effect Equation (MEE) for single- drug, and the Combination Index Equation (CIE) for drug-combinations, are the basis for unified Pharmacodynamics (PD) and Biodynamics (BD). To date, the MAL-PD/BD theory, in 3 articles alone, have 12,577 citations in 1,248 biomedical journals (Google Scholar Citation-Ting-Chao Chou). The applications mainly in vitro, relatively few in vivo [see, ChouTC, Pharmacol Rev. 58: 621-681, 2006 (cited 3,301 times in 914 journals) or Synergy 1: 3-21, 2014]. In recent presentations at JHU (4.9.2019) and at FDA (5.7.2019 & 11.7.2019), Chou presented, the PD-based clinical protocol design using 2-3 dose-data points for single-drug, and 10 data points for 2-drug combinations synergy quantification, e.g., A (3), B (3), and A+B (3), at constant combination ratio, plus a control. For the MAL-PD/BD based protocol design in vivo (dose-range and dose density, combination ratio), the automated CompuSyn simulation/quantitative PD-parameters (for potency and PD-shape)/diagnostic plots/digitalized conclusions/and automated print-out report, usually takes a few seconds, and print-out may take 1-2 minutes. All drugs (chemical, biological, radiation) should have a Dose-Effect curves (DEC). The MEE indicates that all PD-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 (signifying the shape of DEC), and the antilog of x-intercept gives the “Dm” value, (signifying the potency of half-affected). Since MEP linearizes the DEC, it requires a minimum of two data pints to simulate entire DEC. Thus, the Two-Data-Point Theory is extremely cost-effective for in vivo clinical trial protocol designs, as only small number data points is required to achieve efficient computer simulations, with digital/index conclusions. In CIE, CI1, quantitatively defines Synergism, Additive Effect, and Antagonism, respectively, for 2 to n drug combs, using CompuSyn. PD requires multiple doses since “single dose” yields a data-Point, but “a point” has “no shape”, thus, it is never a PD study. Earlier examples with PD-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, which showed similar synergy at ED75 to ED97, CI= 0.82-0.79 for MX-1, and CI= 0.98-0.64 for HCT-116. In conclusion, the MAL-PD/BD and its equations, algorithms and computer simulation provide a rigorous, cost-effective, automated, quantitative biomedical R and D and general drug evaluation guidance in clinical trial design and data analysis, that save resources, time and efforts. Citation Format: Ting-Chao Chou. General pharmacodynamics algorithm-based clinical protocol design with two to three dose-data points for single-drug, and ten data points for two-drug-combination synergy quantification, using computer simulation for digitalized data analysis and conclusions [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 CT155.