Title: Quantifying the effects of compound combinations
Chairman: Joseph Lehár
Completion Date: 2008 - project abandoned
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.