Chapter 31 Plasma Protein Binding and the Free Drug Principle: Recent Developments and Applications

Abstract

Publisher Summary The fundamental premise of the “free drug principle” is that the target occupancy and hence pharmacological activity is responsive to the free or unbound drug concentration at the site of action. An important corollary that derives from the same physical principles is that in the absence of energy-dependent phenomena the free drug concentration will be the same in all compartments that are in steady-state equilibrium. This chapter reports on literature, generally from 2006 to 2007 that supports or refines the understanding of the role of plasma protein binding on drug action in vivo . References to elements of the free drug principle are given where the target plasma levels of drug is discussed. The notion of adjusting plasma exposure/drug potency for plasma protein binding was first introduced in the HIV antiretroviral field. A recent paper discussing the use of inhibitory quotients to optimize HIV therapy stresses the importance of adjusting potencies for plasma protein binding. A number of recent publications indicate that the antibacterial field has adopted the concept of comparing free drug concentration at the site of action to in vitro drug potency reported as MIC. Application of the “free drug principle” is most straightforward for drugs which address extracellular targets since confounding factors such as cell penetration and active transport do not play a role. Examples from the recent medicinal chemistry literature attest to differing levels of engagement ranging from consideration of free fraction as a primary structure–activity relationship (SAR) variable to using plasma protein binding data to rationalize the in vivo activity of an advanced candidate.