Quantitative Methods for Assessing Drug Synergism

Abstract

Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug's potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination.

In Vitro Activities of Primaquine-Schizonticide Combinations on Asexual Blood Stages and Gametocytes of Plasmodium falciparum

“…This deviation from a completely synergistic curve for the PQ-LMF combination in HB3 and 3D7, or "anomalous" isoboles (showing a combination of two types of interactions), may be attributed to the chosen concentrations and paired molar ratios of the two compounds being combined. Ideally, the testing of drug-drug interactions in a combination assay requires titrating serial dilutions to find ratios of concentrations that will produce one specific effect (35,36). This was not performed in our case because we were more interested in how a specific range of PQ-X combinations affects parasite growth.…”

Cannabinoids and Epilepsy

“…However, proper characterization of any "synergistic" effects of multiple plant cannabinoids requires statistically robust demonstrations of effects greater than the sum of the parts. These effects can be tested in vitro or in vivo using assays such as the isobolographic approach [141,142]. Such a design can show if any 2 compounds, extracts, or mixtures are additive in the specific assay (e.g., models of seizure), synergistic, or antagonistic, thereby avoiding speculation about potential synergism or the confusion of additive effects with synergism.…”

Isobolographic Assessment of Interactions Between Retigabine and Phenytoin in the Mouse Maximal Electroshock-Induced Seizure Model and Chimney Test

“…the unpaired Student's t-test was used to statistically compare the ED 50 exp and tD 50 exp values with their respective ED 50 add and tD 50 add values, as reported earlier [18,19]. Similarly, the unpaired Student's t-test was used to statistically analyze total brain concentrations of RtG and PHt in experimental animals.…”

“…thus, interactions between RtG and PHt for three fixed-ratios of 1:3, 1:1 and 3:1 against MES-induced seizures and in the chimney test were analyzed by the use of type I isobolographic analysis for parallel dose-response effects, as described earlier [8]. Briefly, median additive doses for the mixture of RtG with PHt i.e., doses of the mixture, which theoretically should protect 50% of the animals tested against MES-induced seizures (ED 50 add ), or should theoretically impair motor coordination in 50% of the animals tested in the chimney test (tD 50 add ), were calculated and statistically compared with their corresponding experimentally-derived ED 50 exp and tD 50 exp values, as published elsewhere [8,13,18,19]. Subsequently, two parameters: protective index (PI -as a ratio of the respective tD 50 and eD 50 ) and benefit index (BI -as a quotient of PI exp and Pi add ) values were calculated, as described elsewhere [13,16].…”