6.7.2 Pharmacological Dose-Response Parameters

The IC50 is the concentration of a compound that inhibits 50% of a defined enzyme or receptor activity, derived from an inhibition dose-response curve by...

The IC50 is the concentration of a compound that inhibits 50% of a defined enzyme or receptor activity, derived from an inhibition dose-response curve by non-linear regression. The EC50 is the concentration producing 50% of the maximal possible effect, derived analogously from an activation or agonist dose-response curve using the same four-parameter logistic model. The LD50 is the dose that is lethal to 50% of a treated animal population, conventionally derived by probit analysis (the Finney method) or using the AOT425 software associated with OECD Guideline 425, and is expressed in mg/kg. The ED50 is the dose producing the desired therapeutic effect in 50% of a treated population, derived from quantal (all-or-nothing) dose-response data using probit or logit transformation.

Two derived indices are of particular importance in candidate selection. The Selectivity Index (SI) is calculated as the IC50 for cytotoxicity on normal, non-target cells divided by the IC50 for activity on the intended target; an SI greater than 10 is generally regarded as indicating acceptable selectivity for further development. The Therapeutic Index (TI) is calculated as the LD50 divided by the ED50; a higher TI indicates a wider, and therefore safer, margin between the effective and lethal dose, with a TI greater than 10 generally desirable for a new drug candidate, while drugs with a narrow therapeutic index (for example, warfarin or digoxin) require therapeutic drug monitoring in clinical use.