Isobologram Analysis: A Comprehensive Review of Methodology and Current Research

Abstract

Drug combination is a common method for clinical disease treatment. Whether the combination of drugs is reasonable often affects the result of the disease treatment. Many methods have been used to evaluate interaction between drugs to date. Isobologram analysis has been mathematically proven and widely used to evaluate drug interactions. In this paper, the principle of isobologram analysis and its application in drug interaction evaluation are summarized. The applications of the similar cotoxicity coefficient and fractional inhibitory concentration index in the evaluation of drug interaction are also reviewed. This work is expected to evaluate the effect of formulations scientifically and provide scientific judgment standards for the development of formulations and clinical drug compatibility.

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice

“…If the value of the interaction index is less than 0.7 then the interaction is assumed to be synergistic. The interaction index values between 0.7 and 1.3 describe additive interactions, while antagonism is described for interaction index values above 1.3 [28]. For the combination of TPL-16 and valproate, the interaction index was 0.66 indicating a synergistic interaction, which was also confirmed during statistical analysis by means of the Student's t-test (p < 0.05).…”

“…Although both methods in their names have the same word-"isobolographic", they differ significantly. In the isobolographic transformation method, the tested drug is administered at a constant and unchanged dose, which by itself does not have a statistically significant effect on seizure excitability threshold in mice [28,49] (e.g., 5 or 10 mg/kg for TP-427). In the classic isobolographic analysis method, both TPL-16 and classic AED doses increase gradually in a constant ratio of 1:1, so the obtained ED 50 mix value refers to a mixture of both compounds, and not only to a classic AED [50,51].…”

“…Isobolographic analysis is commonly used in evaluating interactions between investigated compounds [28,29]. It compares median additive doses (ED 50 add ), theoretically calculated from the particular ED 50 values of the studied AEDs and TPL-16, to the experimentally determined median effective doses (ED 50 mix ) of TPL-16 and classic AEDs, which reflect the protective (anticonvulsant) effect in 50% of rodents subjected to the MES test.…”

Mathematical Modeling Approaches for Assessing the Joint Toxicity of Chemical Mixtures Based on Luminescent Bacteria: A Systematic Review

“…Dot lines indicate 95% confidential interval of the theoretical additive effect (Mori et al, 2015 ). (D) The theoretical isobologram of the combination of three substances (Huang et al, 2019b ). (E) Isobologram for a mixture of fullerene soot and nonylphenol (Sanchis et al, 2016 ).…”

“…(H) Isobologram for the mixture of fullerene soot and glyphosate (Sanchis et al, 2016 ). Adapted and modified with permission from Ding et al ( 2015 ), Mori et al ( 2015 ), Huang et al ( 2019b ) and Sanchis et al ( 2016 ).…”