Preclinical animal studies or clinical protocol designs frequently limited by the dose-number or dose-range involved, especial for multiple candidate drugs and their combinations. The unified theory of the Mass-Action Law Pharmacodynamics and Bioinformatics [MAL-PD/BI] and its combination index (CI) theory provide general principle for drug evaluation in vitro, in animals and in clinical trials. Thus, all single drugs and their combinations can be compared/ranked under the same MAL-PD principle and the same protocol design-conditions for the unified ranking assessments. Using the MAL-PD/BI/CI and its computer software, anti-HIV combination clinical trials for AZT + 3TC (Mildvan D. et al, Antivir. Ther. 1: 77-88, 1996) was successfully carried out for synergism quantification/simulation (CI<1) using only 36 patients with three-doses each and 10 dose data points. Similar studies in this lab (Synergy 3:15-30, 2016) showed two anti-cancer agents against colon carcinoma HCT-116 xenograft tumors in nude mice, synergy quantification using only 70 mice. Furthermore, anti-HIV drug in vitro for 2 to 5-drug combinations, synergism determination using MAL-PD/CI, have appeared in Chou TC, Pharmacol. Rev. 58: 621-681, 2006. As of Jan. 2, 2021, this article has 3,813 citations in 1,030 biomedical journals. From MAL/median-effect Eq. plot (MEP) with x= log (Dose) vs y= log [(fa)/(1-fa)], where fa is the fraction affected, linearized all dose-effect curves (DEC) with slope =m, and x-intercept = anti-log Dm. Therefore, any two-dose date points on MEP, allow the generation of entire DEC by simulation, where the 3rd point is dose-zero, and the 4th point is the universal Dm point. This is the Minimum Two-Data Point Theory (MTDPT), is the basis for Econo-Green Biomedical R&D and Regulatory Guidance, especially for in vivo studies. Thus, 2 becomes 4, 3 becomes 5, and 4 becomes 6 dose-data points, using small number of dose-data points in clinical protocol design which save time, efforts, resources, and reduced the number of patients for computerized diagnostic plots. To unify the Design and Analysis, now, the same MAL-PD/CI is designed for clinical trial protocol against Covid-19, using Remdesivir, Favipiravir, Dexamethasone, in single drug, two and tree drug combinations (A, B, C, A+B, B+C, A+C and A+B+C, 7 sets). These are with the shared constant combo dose-ratios for 2- and 3-drug combos, and the three doses of each of 7 sets, at the dose range of about 1.5-ED50, 1-ED50 and 0.75-ED50, each with >5 patients, using CompuSyn for instant synergy simulations. The benefit for the MAL-PD/CI is that all single drug and their combinations efficacy/synergy in vitro and in vivo (Covid genetic, antigen or neutralization assays or surrogate markers) are compared/ranked under the same MAL-PD principle and the same protocol design-conditions for the unified ranking assessments. The evaluations of other candidate compounds/agents can be designed and analyzed in the same way, just by adjusting the dose-ranges and the combination-ratios.
Citation Format: Ting-Chao Chou. Pharmacodynamics algorithm integrated assessments-and-ranking of multiple candidate drugs in preclinical and clinical protocol design and quantitative computerized simulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB021.