The importance of plasma protein and tissue binding in a drug discovery program to successfully deliver a preclinical candidate

Abstract

Plasma protein binding and tissue binding are arguably two of the most critical parameters that are measured as part of a drug discovery program since, according to the free drug hypothesis, it is the free drug that is responsible for both efficacy and toxicity. This chapter aims to deconstruct the role of plasma protein and tissue binding in drug discovery programs, and to consider the conclusion made by Pfizer and Genentech/Depomed a decade ago that optimising plasma protein binding as an independent parameter does not significantly influence efficacy. This chapter will also examine how binding metrics are applied in drug discovery programs and explore circumstances where optimising plasma protein or tissue binding can be an effective strategy to deliver a candidate molecule for preclinical development with an early indication of sufficient therapeutic index.

Keywords: Albumin; CNS; Drug discovery; Equilibrium dialysis; Fraction unbound; Free drug hypothesis; K(puu); Neurology; PK/PD; Pharmacodynamics; Pharmacokinetics; Plasma protein binding; Therapeutic index; Tissue binding; Tissue distribution; α-1-Acid glycoprotein.