Figure 2.

Combined effects. (a) Bliss independence and Loewe additivity models for hypothetical drugs D₁ and D₂. Loewe additivity is based on isobolograms depicting the concentrations of D₁ and D₂ needed to produce 50% inhibition (black line). Deviations to the left or right reflect synergy or antagonism, respectively, if Loewe additivity is the model for combined effects. (b) Median-effect plots for D₁ and D₂ alone (solid lines) and predictions of the combined effects of D₁ + D₂ by the Bliss and Loewe models (dotted lines). D₁ and D₂ have slopes of 1 and 1.5, respectively, and are diluted in constant ratio from 10 × C_max which is assumed to be 10 × IC₅₀. (c) Degree of independence (DI) index for quantifying experimental (Exp) combined effects in relations to the models. (d) Representative combination experiments. Drugs were diluted at constant ratio from initial concentrations chosen to maximize the differences between the Bliss and Loewe predictions (see Methods). The figures show experimental measurements for single drugs and combinations (solid lines) and the predictions of the models (dotted lines). These examples illustrate characteristic patterns of Bliss independence (RAL-FTC), Loewe additivity (ETR-NVP), intermediate effect (ABC-NVP), and synergy (AZT-NVP). (e) Expected combination effects based on the binding site criterion. (f) Observed combination effects categorized by DI values: synergy, DI > 1.2; Bliss, 0.8 < DI < 1.2; intermediate, 0.2 < DI < 0.8; Loewe, −0.2 < DI < 0.2, antagonism, DI < −0.2. Because of lower infection with R5-tropic pseudoviruses, PI-MVC combinations could not be analyzed. Individual variation in the combined effect was substantial for some combinations (Supplementary Figure S4).