Basic Principles of Drug Discovery and Development by Blass Benjamin;

Author:Blass, Benjamin; [Blass, Benjamin E.]
Language: eng
Format: epub
Publisher: Elsevier Science & Technology
Published: 2016-05-04T19:51:11+00:00

Figure 6.53 Total plasma exposure after a single oral dose of a compound (AUCoral, blue area) can be compared to the total plasma exposure after a single intravenous dose (AUCIV, green area) in order to determine a compound’s bioavailability. AUC, area under the concentration curve.

Bioavailability data can be used to predict the total exposure of animal to a compound as the dose is increased if there is a linear relationship between the IV and oral doses. When a linear relationship exists, then doubling the oral dose will lead to double the exposure (AUC). In other words, if the 15 mg/kg-dose in Figure 6.54 where to be doubled to 30 mg/kg, the expected AUC would be 3978 ng∗h/mL based on the 82% bioavailability determined at 15 mg/kg. When the relationship is not linear, however, the comparison between an IV dose and a higher oral dose may lead to an apparent %F that exceeds 100%. If, for example, a compound dosed at 5-mg/kg IV and 50-mg/kg oral produces AUCs of 746 ng∗h/mL and 33,562 ng∗h/mL, then the apparent bioavailability of the 50-mg/kg oral dose is 479% (Figure 6.54(b)). The predicted exposure based on a linear relationship would be 7460 ng∗h/mL. The difference between the expected and observed results suggests saturation of an elimination pathway.

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