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

in The AAPS journal by Ling Zou, Huan-Chieh Chien, Devendra Pade, Yanfei Li, Minhkhoi Nguyen, Ravi Kanth Bhamidipati, Zhe Wang, Osatohanmwen Jessica Enogieru, Jan Wahlstrom

TLDR

  • The study found that K-based strategies do not always translate into adequate target coverage and PD effect, highlighting the need for integrative approaches combining K data with comprehensive PK/PD analysis.
  • The study showed that target coverage generally correlates well with PD effect, but K does not
  • K is a better indicator for glioblastoma PD effect than K

Abstract

Kis 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 Kis widely used in the pharmaceutical industry to assess brain exposure, the fidelity of translating Kto target coverage and pharmacodynamic (PD) effect remains uncertain. This study explores the effectiveness of K-based strategies in identifying drug candidates with sufficient target coverage and substantial PD effect. By analyzing reported K, unbound drug concentrations in the brain and ICvalues 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 K, this parameter does not necessarily translate into adequate target coverage (C/IC). In addition, by leveraging PK and PD profiles of 18 drugs measured from human glioblastoma tumors, our study showed that target coverage (glioblastoma C/5xIC) generally correlates well with PD effect. Additionally, Kis a better indicator for glioblastoma PD effect than K, suggesting that intact BBB model may not adequately reflect the barrier heterogeneity in brain tumors such as glioblastoma. In conclusion, while Kprovides an insight on the extent of brain penetration, our study highlighted the need for integrative approaches combining Kdata with comprehensive PK/PD analysis to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.

Overview

  • The study aimed to evaluate the effectiveness of K-based strategies in identifying CNS-targeted drug candidates with sufficient target coverage and substantial pharmacodynamic (PD) effect.
  • The researchers analyzed reported K, unbound drug concentrations in the brain and IC values against pharmacological targets for 17 drugs including anticonvulsants, antidepressants, antipsychotics, and antimicrobials.
  • The primary objective of the study was to explore the fidelity of translating K to target coverage and PD effect and to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.

Comparative Analysis & Findings

  • The study demonstrated that while in vitro and in vivo models work well for rank ordering compounds with high K, this parameter does not necessarily translate into adequate target coverage (C/IC).
  • The researchers found that target coverage (glioblastoma C/5xIC) generally correlates well with PD effect, but K does not.
  • Kis a better indicator for glioblastoma PD effect than K, suggesting that intact BBB model may not adequately reflect the barrier heterogeneity in brain tumors such as glioblastoma.

Implications and Future Directions

  • The study highlights the need for integrative approaches combining K data with comprehensive PK/PD analysis to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.
  • Future studies should consider the applicability of K-based strategies to brain tumors with heterogeneous BBB, such as glioblastoma.
  • Additional research is needed to develop more accurate and representative in vitro and in vivo models that better reflect the complexities of brain penetration and target coverage.
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