Use of Unbound Exposure Data to Establish In Vitro–In Vivo Correlations for CNS Drug Candidates

For a long time, since the introduction of the free drug hypothesis (or free drug theory), it was recognized that the unbound drug concentration in the effect site is much more relevant from a pharmacological viewpoint than total (bound plus unbound drug) exposure. However, for technical reasons, central nervous system drug discovery programs used to rely on estimates of total brain bioavailability, such as the brain-to-plasma concentration ratio at steady state, Kp,brain, or its log-transformation, log BB. Technical advances allowed the measurement or estimation of unbound drug concentrations in the brain, which in turn allowed the introduction of the brain-to-plasma unbound concentration ratio at steady state, Kp,uu,brain, which was progressively adopted and became the dominant parameter used in the industry to establish PK/PD relationships and in vitro–in vivo extrapolations for brain therapeutics. This chapter provides an overview of the free drug theory and the evidence that supports the use of Kp,uu,brain to assist the development of new drugs for central nervous systems disorders. Methods to estimate Kp,uu,brain are also discussed.