2019 PharmSci 360
Recently we have shown that although volume of distribution steady-state (Vss) will change for drug-drug interactions where transporter function is a relevant determinant of drug disposition, this will not be true for metabolic drug-drug interactions where transporter effects are clinically negligible. Thus, for an oral metabolic drug-drug interaction, one is able to determine clearance (CL) divided by bioavailability (F) from dose divided by area under the curve. Using mean residence time concepts it is also possible to determine mean residence time (MRT) and Vss/F if a measurement of mean absorption time (MAT) can be determined, which can be reasonably estimated from a data fit with first order absorption. If the change in Vss/F is calculated and Vss does not change, then the change in F can be estimated, and from the change in CL/F the change in clearance. Confirmations of this new methodology are provided for apixaban and midazolam.