[Frontiers in Bioscience S2, 483-503, January 1, 2010]

A review of synergy concepts of nonlinear blending and dose-reduction profiles

John J. Peterson

Drug Development Sciences Department, Research Statistics Unit (UP-4315), GlaxoSmithKline Pharmaceuticals, R&D, 1250 So. Collegeville Road, Collegeville, Pennsylvania 19426, USA


1. Abstract
2. Introduction
2.1. Two classical approaches to synergy
2.2. A nonlinear blending approach to drug synergy
2.3. A dose reduction profile approach to compound blending
3.Response surface modeling
3.1. The molar-unit Minto-White model
3.2. Low folic acidexperiment
3.3. High folic acidexperiment
4.Nonlinear blending analysis
4.1. Strong nonlinear blending
4.2. Low folic acidexperiment
4.3. High folic acidexperiment
5.Analysis of dose reduction profiles
5.1. Dose reduction profile curves
5.2. Low folic acidexperiment
5.3. High folic acidexperiment
6. Summary and perspective
7. Acknowledgements
8. References


This article presents a case-study review of synergy concepts of nonlinear blending and dose-reduction profiles. "Strong nonlinear blending" is a novel concept that provides a flexible paradigm for the assessment of combination drug synergy that is applicable to any shaped combination-drug dose-response surface; issues of varying relative potency, partial inhibitors, potentiation, or coalism pose no problems at all. Dose-reduction profiles are overlay plots created to show how much each drug can be reduced in amount and yet achieve the same efficacy as larger amounts of each drug used individually. This review applies these synergy concepts to two data sets from a previously published experiment. The previous publication had claimed a high degree of Loewe synergy for one of the data sets. However, a more penetrating analysis shows that with regard to strong nonlinear blending there is no reason to blend (for purposes of response enhancement) the two compounds studied. However, the dose-reduction profile plots show how Loewe synergy is present and provide further insight to the interaction of the two compounds (on the dose-concentration scale).