Comparison of methods for evaluating drug-drug interaction.

The goal of the present report is to compare several published methods of analyzing drug-drug interaction data. The compared methods are the curve-shift analysis, isobologram, combination index, and universal surface response analysis, and the comparison was based on analysis of published cytotoxicity data of combinations of two anti-folate agents. Major findings are as follows. The curve shift analysis enabled the inspection of the experimental data and visual evaluation of the approximate parallelism between the dose response curves. Isobologram analysis provided the range of concentration ratios where maximal synergy was obtained. The combination index analysis readily provided quantitative estimation of the extent of synergy or antagonism. The universal surface response method summarized drug-drug interaction in a single parameter, facilitating comparison of larger arrays of combinations. Only the curve shift analysis and the universal surface response method yielded a statistical estimate of differentiation between synergy, additivity, and antagonism. In summary, curve shift analysis, isobolograms, combination index analysis, and the universal response surface method are useful methods for analyzing drug-drug interaction, and provide complementary information.