Considerations in Kp,uu,brain-based Strategy for Selecting CNS-targeted Drug Candidates with Sufficient Target Coverage and Substantial Pharmacodynamic Effect.

Kp,uu,brain is a critical parameter for evaluating the brain penetration of CNS-targeted compounds, reflecting the ratio of unbound drug concentration in the brain to that in the plasma. While Kp,uu,brain is widely used in the pharmaceutical industry to assess brain exposure, the fidelity of translating Kp,uu,brain to target coverage and pharmacodynamic (PD) effect remains uncertain. This study explores the effectiveness of Kp,uu,brain-based strategies in identifying drug candidates with sufficient target coverage and substantial PD effect. By analyzing reported Kp,uu,brain, unbound drug concentrations in the brain and IC50 values against pharmacological targets for 17 drugs including anticonvulsants, antidepressants, antipsychotics, and antimicrobials, our study demonstrated that while in vitro and in vivo models work well for rank ordering compounds with high Kp,uu,brain, this parameter does not necessarily translate into adequate target coverage (Cu/IC50). In addition, by leveraging PK and PD profiles of 18 drugs measured from human glioblastoma tumors, our study showed that target coverage (glioblastoma Cu/5xIC50) generally correlates well with PD effect. Additionally, Kp,uu,brain tumor is a better indicator for glioblastoma PD effect than Kp,uu,brain, suggesting that intact BBB model may not adequately reflect the barrier heterogeneity in brain tumors such as glioblastoma. In conclusion, while Kp,uu,brain provides an insight on the extent of brain penetration, our study highlighted the need for integrative approaches combining Kp,uu,brain data with comprehensive PK/PD analysis to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.