When the combined effect of two drugs each producing the same biological response by the same mechanism of action is equal to the sum of their individual effects?

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Page 2

The most commonly utilized drug synergy detection and quantification methods

	Concept	Assumptions	Equations	Limitations	Reference
Bliss independence	Idea of no interaction (each drug is acting independently of one another)	(i) The drug effect achieved by the probability that two drugs do not interfere with each other(ii) The combined drugs have a different site/ mechanism of action in achieving the effect (iii) Drugs have exponential dose–effect curves	EA + EB(1 − EA) = EA + EB − EAEB CI = (EA + EB − EA x EB)/EAB	Model is applicable solely to effects expressed as probabilities between 0 and 1In many drug interactions drug dependence cannot be excludedThe model must be applicable along the entire dose response curve The model does not work in a `sham mixture’ situation	[13]
Loewe additivity	`Sham mixture’ — no expectation of any type of interaction	(i) Drug cannot interact with itself(ii) Constant potency ratio at all doses (iii) Equal individual drug maximum effects	EAB = EA(a + ab) = EB(ba + b) a + ab = A ↔ a + b x R = A ↔ a + b x A/B = A a/A + b/B = 1 CI = a/A + b/B	Relies on precisely estimated dose–effect curves — thus not applicable when a dose-effect curve is not available R is not always constant and is rather the exception	[12]
Highest single agent (HAS)	The resulting effect of a drug combination is superior than the effects achieved by the individual drugs	Synergistic drug combination should produce additional result on top of what its components can produce alone	EAB = max(EA,EB) CI = max(EA,EB)/EAB	Often a drug combined with itself can produce an excess over HASFrequently fails to establish an improved drug combination effect in comparison to the expected additive effect of its components Any extra effect over the higher single drug will be considered as synergy	[11]
Chou-Talalay	Based on the median-effect equation and mass-action law	Drugs should have a constant potency ratio	fa/fu = (D/Dm)m* CI = D1/E1 + D2/E2	Dose response curves are primarily non-linear, thus difficult to correctly calculate the median effect dose and the sigmoidicity of the dose–effect curve	[14, 15, 16]