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Analysis of drug combinations: current methodological landscape.

Foucquier J, Guedj M - Pharmacol Res Perspect (2015)

Bottom Line: In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest.Here, we propose an overview of the current methodological landscape concerning the study of combination effects.First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect-based approaches and dose-effect-based approaches, and introduced in light of their respective practical advantages and limitations.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics and Biostatistics, Pharnext Issy-Les-Moulineaux, France.

ABSTRACT
Combination therapies exploit the chances for better efficacy, decreased toxicity, and reduced development of drug resistance and owing to these advantages, have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need. In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest. Research in this field has resulted in a large number of papers and revealed several issues. Here, we propose an overview of the current methodological landscape concerning the study of combination effects. First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect-based approaches and dose-effect-based approaches, and introduced in light of their respective practical advantages and limitations. Then, we discuss six main common methodological issues that scientists have to face at each step of the development of new combination therapies. In particular, in the absence of a reference methodology suitable for all biomedical situations, the analysis of drug combinations should benefit from a collective, appropriate, and rigorous application of the concepts and methods reviewed here.

No MeSH data available.


Related in: MedlinePlus

Illustration of the four effect-based approaches. (A) Combination Subthresholding, (B) Highest Single Agent, (C), Response Additivity, and (D) Bliss Independence. Based on EA = 30, EB = 20, and EAB = 65. NS, Nonsignificant; *, Significant at the 5% level.
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fig01: Illustration of the four effect-based approaches. (A) Combination Subthresholding, (B) Highest Single Agent, (C), Response Additivity, and (D) Bliss Independence. Based on EA = 30, EB = 20, and EAB = 65. NS, Nonsignificant; *, Significant at the 5% level.

Mentions: Methods following an effect-based strategy compare the effect resulting from the combination of two drugs (EAB) directly to the effects of its individual components (EA and EB). The exact decision process that allows a conclusion of positive, negative, or combination effect can vary among four main strategies which are (1) Combination Subthresholding, (2) Highest Single Agent, (3) Response Additivity, and (4) Bliss Independence model described hereafter and illustrated in Figure1.


Analysis of drug combinations: current methodological landscape.

Foucquier J, Guedj M - Pharmacol Res Perspect (2015)

Illustration of the four effect-based approaches. (A) Combination Subthresholding, (B) Highest Single Agent, (C), Response Additivity, and (D) Bliss Independence. Based on EA = 30, EB = 20, and EAB = 65. NS, Nonsignificant; *, Significant at the 5% level.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492765&req=5

fig01: Illustration of the four effect-based approaches. (A) Combination Subthresholding, (B) Highest Single Agent, (C), Response Additivity, and (D) Bliss Independence. Based on EA = 30, EB = 20, and EAB = 65. NS, Nonsignificant; *, Significant at the 5% level.
Mentions: Methods following an effect-based strategy compare the effect resulting from the combination of two drugs (EAB) directly to the effects of its individual components (EA and EB). The exact decision process that allows a conclusion of positive, negative, or combination effect can vary among four main strategies which are (1) Combination Subthresholding, (2) Highest Single Agent, (3) Response Additivity, and (4) Bliss Independence model described hereafter and illustrated in Figure1.

Bottom Line: In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest.Here, we propose an overview of the current methodological landscape concerning the study of combination effects.First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect-based approaches and dose-effect-based approaches, and introduced in light of their respective practical advantages and limitations.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics and Biostatistics, Pharnext Issy-Les-Moulineaux, France.

ABSTRACT
Combination therapies exploit the chances for better efficacy, decreased toxicity, and reduced development of drug resistance and owing to these advantages, have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need. In this context, studying the effects of a combination of drugs in order to provide evidence of a significant superiority compared to the single agents is of particular interest. Research in this field has resulted in a large number of papers and revealed several issues. Here, we propose an overview of the current methodological landscape concerning the study of combination effects. First, we aim to provide the minimal set of mathematical and pharmacological concepts necessary to understand the most commonly used approaches, divided into effect-based approaches and dose-effect-based approaches, and introduced in light of their respective practical advantages and limitations. Then, we discuss six main common methodological issues that scientists have to face at each step of the development of new combination therapies. In particular, in the absence of a reference methodology suitable for all biomedical situations, the analysis of drug combinations should benefit from a collective, appropriate, and rigorous application of the concepts and methods reviewed here.

No MeSH data available.


Related in: MedlinePlus