A review of synergy concepts of nonlinear blending and dose-reduction profiles.
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).
Peterson
John J
JJ
Drug Development Sciences Department, Research Statistics Unit (UP-4315), GlaxoSmithKline Pharmaceuticals, Rand D, 1250 So Collegeville Road, Collegeville, Pennsylvania 19426, USA. john.peterson@gsk.com
D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D005492:Folic Acid; D005971:Glutamates / Q000494:pharmacology; D008962:Models, Theoretical; D011743:Pyrimidines / Q000494:pharmacology; D016597:Trimetrexate / Q000494:pharmacology
D004338:Drug Combinations; D005971:Glutamates; D011743:Pyrimidines; D005492:Folic Acid; C105066:AG 2034; D016597:Trimetrexate