Consideration of the Linear Concentration Increase of the Unbound Drug Fraction in Plasma

The concentration of drug in plasma may not necessarily be much less than that of the drug binding proteins, as often considered. Thus the unbound drug fraction could be concentration dependent, which should be taken into account in the interpretation of drug pharmacokinetics and modeling. It is shown that the increase of the unbound drug fraction, fu, can be very accurately considered proportional to the drug plasma concentration for a relatively wide range of concentrations. Equations for the calculation of fu in this linear range are obtained, as well the limiting drug concentration when the linear approximation of fu is applicable. The suggested approach greatly simplifies the calculation of fu and can be ready used in pharmacokinetic calculations and PK‐PD models, as well as for the prediction of the change of fu due to the variation of protein concentrations in plasma. Naproxen protein binding in human plasma is considered as an illustration of the method. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:383-393, 2009