(544.1) MAL-pharmacodynamics theory based small-size experimental-design and analysis, in vitro, in animals and in clinical trial, with bioinformatics algorithm, for automated computer simulation to achieve quantitative/digital/indexed conclusions

Poster Board Number: B177

Ting-Chao Chou (Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center)

The conventional bottom-to-up approach of Ramp;D is usually from aims to design, to experimental findings, to fitting empirical curves, formula, or model, to statistical analysis, to drawing conclusion/hypothesis. The alternative nonconventional, top-to-down approach is the mathematical system analysis to derive the unified general pharmacodynamics theory/equation/algorithm (PD) based on mass-action law (MAL) for automated computer simulation. Thus, the approach allows using small number of dose-data–points to fit the unified MAL-PD theory/algorithm, for the efficient, cost-effective automated computer simulation to achieve quantitative/digital/indexed conclusions. The MAL-PD indicates: (I) The median-effect eq. (MEE) “dose-effect dynamics” defines PD-parameters: Dm (median-effect-dose) for potency, and m value for the dynamic-order signifying the shape of dose-effect curve (DEC), where m=1, gt;1 and lt;1 indicate hyperbolic, sigmoidal and flat sigmoidal, respectively, and (II) Computer simulation of combination index eq. (CIE) with Fa-CI plot, allow the quantification of Synergism (CIlt;1), Additive effect (CI=1) and Antagonism (CIgt;1) at different effect levels. The advantages of MAL-PD approach are: (A) In animal studies or clinical trials rarely tolerated over 3 (or more) “dose-data points” with acceptable dose-rage and dose density; (B) MAL theory/algorithm allows the same general MAL-principle to bridge between the basic in vitro/animal studies and the clinical trials; (C) The MEE with its plot (MEP), linearizes DECs into straight lines, and thereby MEP leads to the “Two Dose-Data-Points Minimum Theory”, where the 3rd point is dose zero, and the 4th dose-point is Dm, which is the universal reference-point and dynamic-order common-link; (D) Since all terms of the MEE and CIE of the MAL-PD equations are “dimensionless ratio”,  therefore, MAL-PD/CI is generally valid/applicable in Ramp;D, regardless of nature of the effectors (e.g., drugs, biologicals, radiation, UV, pH) or units (e.g., ug, nM, IU, Rad, Gy, ug/ml, mg/kg. mg/M2), or mechanisms of action (competitive, noncompetitive, uncompetitive, sequential, ordered, ping-pong, or random); and regardless of in vitro, in animals, or in clinical trials. In conclusion, the MAL-PD/CI theory serves as the general largest-common-denominator for simplifying the complexity and diversity of biological systems, for biomedical Ramp;D, and for drug evaluations, with automated simulations. Specific examples for real data analysis/simulation in vitro, and in animals will be illustrated for single drugs, and their combinations, for anticancer and antiviral studies.

Memorial Sloan-Kettering Cancer Center General Core Fund.