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. Graphical Abstract a-c: in vitro trans-well, in vivo rodent and non-human primate models, and CSF from non-human primate or human, to predict human Kp,uu,brain. The arrows with solid line represent reasonable prediction. d: For oncology programs that develop drugs targeting brain tumors, Kp,uu,brain is commonly used for prioritizing compounds, assuming that Kp,uu,brain tumor would be higher or similar to Kp,uu,brain, which provides conservative estimate of brain tumor penetration. The arrow with dashed line represents that there is limited information about the effectiveness of Kp,uu,brain as a surrogate of Kp,uu,brain tumor. e–f: Translation of Kp,uu,brain and Kp,uu,brain tumor to target coverage. Arrows with dashed line represent that there is limited information about the direct correlation. g: Translation of target coverage to PD effect. The arrow with solid line represents reasonable translation.

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

期刊论文
发表日期：

2025年2月28日

查看全文

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

摘要

K_p,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 K_p,uu,brain is widely used in the pharmaceutical industry to assess brain exposure, the fidelity of translating K_p,uu,brain to target coverage and pharmacodynamic (PD) effect remains uncertain. This study explores the effectiveness of K_p,uu,brain-based strategies in identifying drug candidates with sufficient target coverage and substantial PD effect. By analyzing reported K_p,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 K_p,uu,brain, this parameter does not necessarily translate into adequate target coverage (C_u/IC₅₀). In addition, by leveraging PK and PD profiles of 18 drugs measured from human glioblastoma tumors, our study showed that target coverage (glioblastoma C_u/5xIC₅₀) generally correlates well with PD effect. Additionally, K_{p,uu,brain tumor} is a better indicator for glioblastoma PD effect than K_p,uu,brain, suggesting that intact BBB model may not adequately reflect the barrier heterogeneity in brain tumors such as glioblastoma. In conclusion, while K_p,uu,brain provides an insight on the extent of brain penetration, our study highlighted the need for integrative approaches combining K_p,uu,brain data with comprehensive PK/PD analysis to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.

Graphical Abstract

a-c: in vitro trans-well, in vivo rodent and non-human primate models, and CSF from non-human primate or human, to predict human K_p,uu,brain. The arrows with solid line represent reasonable prediction. d: For oncology programs that develop drugs targeting brain tumors, K_p,uu,brain is commonly used for prioritizing compounds, assuming that K_{p,uu,brain tumor} would be higher or similar to K_p,uu,brain, which provides conservative estimate of brain tumor penetration. The arrow with dashed line represents that there is limited information about the effectiveness of K_p,uu,brain as a surrogate of K_{p,uu,brain tumor}. e–f: Translation of K_p,uu,brain and K_{p,uu,brain tumor} to target coverage. Arrows with dashed line represent that there is limited information about the direct correlation. g: Translation of target coverage to PD effect. The arrow with solid line represents reasonable translation.

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

摘要

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