An Overview of Drug Combination Analysis with Isobolograms

Drugs given in combination may produce effects that are greater than or less than the effect predicted from their individual potencies. The historical basis for predicting the effect of a combination is based on the concept of dose equivalence; i.e., an equally effective dose (a) of one will add to the dose (b) of the other in the combination situation. For drugs with a constant relative potency, this leads to linear additive isoboles (a-b curves of constant effect), whereas a varying potency ratio produces nonlinear additive isoboles. Determination of the additive isobole is a necessary procedure for assessing both synergistic and antagonistic interactions of the combination. This review discusses both variable and constant relative potency situations and provides the mathematical formulas needed to distinguish these cases.