Mass‐Action Law Based Pharmacodynamics General Theory, Equation, Algorithm, and Computer Simulation for Econo‐Green Biomedical R&D and for Quantitative/indexed Drug Evaluation Guidance

Abstract

The Mass‐Action Law (MAL) based Median‐Effect Equation (MEE) is the Unified General Theory of Pharmacodynamics (PD) ‐‐Biodynamics (BD) – Bioinformatics (BI) (MAL‐PD/BD/BI) [Chou TC, Pharmacol. Rev. 58: 621–681, 2006]. The derived MEE yields the algorithms that provide efficient, quantitative, econo‐green, digital, automated computer simulations for bio‐medical research & development (R&D). Its extension yields Combination Index Equation (CIE), which quantitatively defines drug combination synergy (CI<1), additive effect (CI=1) and antagonism (CI>1) [in: Chou TC and Talalay P. Adv. Enz. Regul. 22: 27–55, 1984], which has been cited 6,275 times in over 1,249 biomedical journals worldwide, encompassing nearly all disciplines of biomedical sciences, as of Oct. 2, 2019. The derived MEE theory reveals the following new basic paradigms: 1. “Dose” and “Effect” are interchangeable. 2. All dose‐effect curves of MAL can be transformed into straight lines.3. The theoretical minimum of only 2‐data points are required to simulate a dose‐effect curve, where the 3rd point is Dose Zero, and the 4th point is the median‐effect dose (Dm), which is the universal reference‐point and the dynamic common‐link. 4. The fact that only 2‐data‐points theory are required to simulate a dose‐effect curve, is of particularly importance, since fewer number of doses are needed in animals studies or in clinical protocol trial designs. 5. It is noted that most clinical trials had used only single dose. However, a single dose (for a single drug or for a drug‐combination dose) generates a Potency “Point”, but a “point” has no “shape”, and PD requires both “Potency” and “Shape”. 6. The PD indicates that Phase I clinical trial protocol‐design shall use 2 to 3 doses for single drug, and only ten doses (3+3+3+1=10) for two‐drug combination synergy quantification, using Chou‐Talalay combination index (CI) method and computer software. Thus, the new PD paradigm is the theoretical basis for simple, efficient, quantitative “econo‐green” bio‐R&D and drug PD parameter evaluations. 7. The explicit digital definition of “Synergism” of drug combination is now established. 8. The PD software, e.g., CompuSyn, allows automated generations of five graphic transformations for diagnostic plots [i.e., the dose‐effect curves, the median‐effect plots (for curve linearization), the CI‐Plot and the Isobologram (for synergy/antagonism determination), as well as the DRI‐Plot (for the dose‐reduction calculation in synergistic combinations). These automatic illustrations by computer simulation is completed within 1 second after data entries. Thus, the MAL‐PD/BD unified general theory is proven to have broad and cost‐effective utilities in biomedical R&D, provide automated quantitative/indexed basic parameters, diagnosis and conclusions for drug evaluations, and streamline the drug‐evaluation regulatory processes.Support or Funding InformationSelf Funding (Retired Professor)The Mass‐Action Law PD/BD Theory, Equations, and New Paradigm Revelations.Figure 1Mass‐Action Law Based Pharmacodynamics, Biodynamics and Bioinformatics Theory: Applications, Citation Metrics and Trend.Figure 2