Project Details:

Quantifying the effects of compound combinations

Project No.:	2003-059-1-700
Start date:	2004-04-01
End date:	2008-12-30
Division:	Chemistry and Human Health Division

To recommend standard descriptions and reference models for quantifying the effects of compounds in combination.

The past three decades have seen considerable debate on how to describe the effects of compound combinations [see Greco et al. 1995, Pharm. Rev. 47(2):331-385]. Much of the discussion was focused on which is the best reference model for combination response surfaces, as predicted from the single agent dose-response curves. Most clinical researchers preferred the compound-against-itself based Loewe additivity reference for synergy [Loewe 1953, Arzneim. Forsch. 3:285], especially using the Combination Index method [Chou & Talalay 1984, Adv. Enz. Reg. 22:27]. A smaller number of investigators favoured other models, notably the statistically-derived Bliss independence [Bliss, 1939, Ann. Appl. Biol. 26:585].

Some resolution was achieved by a working group convened in Saariselskä, Finland [Greco et al. 1992, Arch. Complex Env. Stud. 4:65], which defined standards for describing combination effects. They placed the Loewe and Bliss models on an equal footing, and described effects depending on the single agent activity levels.

However, the Saariselskä group left open the problem of quantifying the many observed effects that defy description by either of the accepted standard models. Rather than simply exceeding or falling short of one of the standards, many observed effects alternate between synergy and antagonism depending on the relative concentrations of the compounds. The standard reference models also can't describe coalism effects, where two inactive agents give rise to a combined effect that could never be predicted from the single agent dose responses. Evidently, the standard combination references cannot account for the wide variety of empirical contexts.

A more general approach to describing combination effects is to compare the observed response surface to those from a range of theoretical combinations, each appropriate to different mechanistic assumptions. In the biological context, the measured effect of combined compounds will depend on the connection between the agents' targets. For example, Loewe additivity describes the result of two compounds sharing a target, while Bliss independence might be expected for separate targets with no physical or chemical connection. There are, of course, many other possible relationships between the targets, leading to the range of observed combination effects.

We propose to prepare an IUPAC recommendation endorsing the nomenclature resulting from the Saariselskä agreement. We further propose to recommend a predictive response surface approach to quantifying combination effects, based on a simple system of target connections, and to present some sets of models that are appropriate to networks of biological reactions.

Of relevance to this project, Lehar and Keith were recently involved in the following work: 'Chemical combination effects predict connectivity in biological systems' Mol Syst Biol. 2007; 3: 80 [doi: 10.1038/msb4100116] and 'Multi-target therapeutics: when the whole is greater than the sum of the parts' Drug Discov Today 2007 Jan;12(1-2):34-42 [doi: 10.1016/j.drudis.2006.11.008].
In this latest review, the authors discuss the biological rationale for combination therapeutics, review some existing combination drugs and present a systematic approach to identify interactions between molecular pathways that could be leveraged for therapeutic benefit.
A draft outcome for this project is anticipated by the end of 2007.

> project announcement published in Chem. Int. Jul-Aug 2004 issue>

December 2008 - Project abandoned