The linear concentration–effect model, underpinned by the principle that pharmacological effect (E) is directly proportional to plasma drug concentration (C), emerges as a pivotal simplification of the Emax model for conditions where C is significantly less than EC50. This model portrays a linear trajectory of the concentration–effect relationship when drug levels are markedly below the EC50 threshold.
Despite its inherent assumption of continuous effect augmentation with increasing drug concentrations up to a maximal effect (Emax), the model acknowledges the practical limitations of its linearity across extensive concentration ranges. As a result, it confines its applicability to comprehensive pharmacodynamic modeling. However, its utility is exemplified in the precise evaluation of drug-induced cardiac repolarization effects, as measured by the QT interval on electrocardiograms. It has been extensively applied in characterizing the concentration-QTc relationship for moxifloxacin and developing new pharmacological entities.
The concentration-QTc analysis facilitates the US FDA's regulatory review processes, particularly in assessing the proarrhythmic risks associated with novel therapeutic agents, underscoring its significance in advancing drug safety evaluations.
The linear concentration-effect model assumes that the pharmacological effect, E, is directly proportional to the plasma drug concentration, Cp.
When plotting the plasma drug concentration against an effect, the concentration-effect curve is approximately linear below EC50.
The model posits that the drug's effect increases continually with rising concentrations until reaching the maximum pharmacological effect, Emax.
However, this linear relationship does not hold across a wide range of concentrations.
Despite these limitations, the model is widely used to evaluate drug effects on cardiac repolarization, measured by the QT interval on an electrocardiogram or ECG.
For example, under this model, the plot between moxifloxacin concentration and QTc interval prolongation yields a linear curve.
Also, the concentration-QTc relationship plays a key role in the FDA’s regulatory evaluation of new drugs for assessing proarrhythmic risk.
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