Assessing the Joint Action of Multiple Drugs: Synergy, Additivity, and Antagonism

• Activity Number: 305
• Type: Contributed
• Date/Time: Wednesday, August 11, 2004 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Xiaoli S. Hou*+ and Keith A. Soper
• Companies: Merck & Co., Inc. and Merck & Co., Inc.
• Keywords: synergy ; additive ; antagonism ; response additive ; concentration additive ; interaction

Abstract

A new "segmented response surface" approach is proposed for measurement of the joint effect of two or more drugs in vitro: synergy, additivity, or antagonism. Widely used approaches based on response surface methods either parameterize how drugs interact, resulting in poor conclusions when the true interaction is more complex than assumed, or use a nonparametric response surface method that lacks power and often is difficult to summarize. Our approach compares simple dose-response curves such as the response curve for drug "A" alone vs. at fixed combinations of drugs "B," "C," etc, vs. the dose-response predicted by "additivity." Our graphical results are easy to explain and have direct clinical interpretation. Our method easily detects when drugs may be synergistic at some doses but antagonistic at other doses. We show how to construct a single map partitioning the observed dose-space into "smooth" regions of synergy, additive, subadditive, inert, and interference that is consistent with all dose response curves regardless of which compounds are fixed and which allowed to vary. Associated statistical tests are more powerful than competing standard methods in realistic situations.