Limits...
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 Loewe Additivity. (A) Dose–effect curves for two drugs A and B (here with constant potency ratio R) allow estimation of the single doses AE and BE reaching the combination effect E produced by the combination of doses a of drug A and b of drug B. (B) Isobologram analysis at the combination effect E. The single doses AE and BE are used to draw the line of additivity. The localization of the experimental point (a, b) corresponding to the doses actually needed for a combination effect E with respect to the line of additivity can be translated in term of synergy, additivity, and antagonism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492765&req=5

fig03: Illustration of the Loewe Additivity. (A) Dose–effect curves for two drugs A and B (here with constant potency ratio R) allow estimation of the single doses AE and BE reaching the combination effect E produced by the combination of doses a of drug A and b of drug B. (B) Isobologram analysis at the combination effect E. The single doses AE and BE are used to draw the line of additivity. The localization of the experimental point (a, b) corresponding to the doses actually needed for a combination effect E with respect to the line of additivity can be translated in term of synergy, additivity, and antagonism.

Mentions: Loewe Additivity rests on both the dose equivalence principle (that for a given effect, dose a of drug A is equivalent to dose ba of drug B, and reciprocally) and the sham combination principle (that ba can be added to any other dose b of drug B to give the additive effect of the combination). The additive effect of drugs A and B depends on the individual dose–effect curves and can be expressed as:where EA is measured on the dose–effect curve of drug A, (a + ab) corresponds to the dose A giving the effect EAB and, respectively, for drug B. It makes the assumption that the drugs have a constant potency ratio (). In practice, dose–effect curves with constant potency ratio have a constant ratio of doses at every level of effect and hence are parallel on a log-dose scale, and have equal individual drug maximum effects (Fig.3A) (Tallarida 2012). From there, we can easily define the following relation between all pairs of doses (a, b) producing the combination effect EAB and the single doses A and B necessary to reach this effect:which leads to the most influential mathematical relation of the Loewe Additivity at the basis of most dose–effect-based approaches developed subsequently:


Analysis of drug combinations: current methodological landscape.

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

Illustration of the Loewe Additivity. (A) Dose–effect curves for two drugs A and B (here with constant potency ratio R) allow estimation of the single doses AE and BE reaching the combination effect E produced by the combination of doses a of drug A and b of drug B. (B) Isobologram analysis at the combination effect E. The single doses AE and BE are used to draw the line of additivity. The localization of the experimental point (a, b) corresponding to the doses actually needed for a combination effect E with respect to the line of additivity can be translated in term of synergy, additivity, and antagonism.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Illustration of the Loewe Additivity. (A) Dose–effect curves for two drugs A and B (here with constant potency ratio R) allow estimation of the single doses AE and BE reaching the combination effect E produced by the combination of doses a of drug A and b of drug B. (B) Isobologram analysis at the combination effect E. The single doses AE and BE are used to draw the line of additivity. The localization of the experimental point (a, b) corresponding to the doses actually needed for a combination effect E with respect to the line of additivity can be translated in term of synergy, additivity, and antagonism.
Mentions: Loewe Additivity rests on both the dose equivalence principle (that for a given effect, dose a of drug A is equivalent to dose ba of drug B, and reciprocally) and the sham combination principle (that ba can be added to any other dose b of drug B to give the additive effect of the combination). The additive effect of drugs A and B depends on the individual dose–effect curves and can be expressed as:where EA is measured on the dose–effect curve of drug A, (a + ab) corresponds to the dose A giving the effect EAB and, respectively, for drug B. It makes the assumption that the drugs have a constant potency ratio (). In practice, dose–effect curves with constant potency ratio have a constant ratio of doses at every level of effect and hence are parallel on a log-dose scale, and have equal individual drug maximum effects (Fig.3A) (Tallarida 2012). From there, we can easily define the following relation between all pairs of doses (a, b) producing the combination effect EAB and the single doses A and B necessary to reach this effect:which leads to the most influential mathematical relation of the Loewe Additivity at the basis of most dose–effect-based approaches developed subsequently:

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