Computerized quantification of drugs synergism in animal studies or in clinical trials using only ten data points

Ting Chao Chou, Theresa A Shapiro, Jianing Fu, Joseph H. Chou, Gudrun S. Ulrich-Merzenich

Research output: Contribution to journalReview article

Abstract

The median-effect equation (MEE) derived from the mass-action law (MAL) is the unified theory of dose-effect pharmacodynamics (PD) and biodynamics (BD). MEE enables the linearization of a dose-effect curve into a straight linedefined by two data points. Thus any two data points can represent an entire dose-effect curve. For dose-effect curves using MAL, dose-zero can serve as 3rd point, and the universal reference point, the median-effect dose (Dm) serves as 4th point. This functionality has tremendous significance for in vivo studies. Fewer data points are required for a dose-effect curve, facilitating economical and ethically sustainable PD analyses. The extension of MEE from a single drug to multiple drugs establishes the general combination index equation (CIE), which quantitatively defines synergism (CI < 1), additive effect (CI = 1) and antagonism [CI > 1]. Although the CI method is often (>6000 citations) applied in in vitro studies, it is rarely used in animal studies or clinical trials. In vivo drug combination studies that use only single dose or statistical p value analyses do not allow quantitative synergy claims. This article presents two examples for drug combinations in vivo: (i) in animals (anticancer drug combination against human HCT-116 colon carcinoma xenografts in nude mice, Taxotere + T607) and (ii) in a clinical trial (anti-retroviral drug combinations against HIV/AIDS, AZT + INF). Only 36 patients respectively only 66 nude mice were required. Both examples require only ten data points (D1, D2 and [D1+D2], each with 3 doses plus one control) to quantitatively determine synergism or antagonism with the CompuSyn software.

Original languageEnglish (US)
Article number100049
JournalSynergy
Volume9
DOIs
Publication statusPublished - Dec 1 2019

    Fingerprint

Keywords

  • Combination index
  • CompuSyn software
  • Drug combination in animals
  • Drug combination in clinical trials
  • Synergy computation
  • Synergy definition
  • Synergy quantitation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Molecular Biology
  • Cell Biology
  • Pharmacology (medical)

Cite this