Exploring various measures of the area under the curve for the assessment of dose-proportionality and estimation of bioavailability

Abstract Objective In pharmacokinetics, the area under the concentration versus time curve (AUC) extrapolated to infinity (AUC0−∞) is the preferred metric but it is not always possible to have a reliable estimate of the terminal phase half-life. Here we sought to explore the accuracy of three different area measures to accurately identify dose proportionality and bioavailability. Methods One to three compartment model simulations with different doses for dose-proportionality or different rates and/or extents of bioavailability. Area measures evaluated were AUC0−∞, to the last quantifiable concentration (AUCtlast), and to a common time value (AUCt’). Results Under linear pharmacokinetics, AUCt’ provided the most accurate measure of dose proportionality. Except for the one compartment model where AUC0−∞ provided the best predictor of the true measure, there was no clear advantage to the use of either of the three measures of AUC. Conclusion With uncertainty about the terminal phase half-life, the use of AUCt’ can be a very useful and even the preferred measure of exposure for use in assessing proportionality in exposure between doses. The choice of AUC measure in bioavailability is less clear and may depend on compartmental nature of the drug, and study parameters including assay sensitivity and sampling protocols. Graphical Abstract Graphical Abstract