CSF as a surrogate for assessing CNS exposure: an industrial perspective

Area of Science:

• Pharmacology
• Neuroscience
• Drug Discovery

Background:

• Effective central nervous system (CNS) drug action necessitates adequate brain delivery.
• The blood-brain barrier (BBB) regulates systemic drug entry into the CNS.
• Marketed CNS drugs often exhibit good membrane permeability and high unbound plasma fraction but are poor P-glycoprotein (P-gp) substrates.

Purpose of the Study:

• To highlight the importance of in vitro parameters for CNS drug discovery lead optimization.
• To evaluate the utility of cerebrospinal fluid (CSF) drug concentration as a surrogate for brain exposure.
• To identify limitations of using CSF drug concentration for predicting brain exposure.

Main Methods:

• Review of literature data on CNS drug properties and delivery.
• Analysis of preclinical and clinical evidence on CSF drug concentration as a predictor of brain exposure.
• Consideration of in vitro parameters: P-gp function, membrane permeability, and plasma unbound fraction.

Main Results:

• In vitro parameters like P-gp activity, membrane permeability, and unbound fraction are crucial for early-stage CNS drug optimization.
• CSF drug concentration is often a reasonable predictor of unbound brain drug concentration.
• CSF drug concentration may not always accurately reflect unbound brain drug concentration due to drug properties and sampling variations.

Conclusions:

• In vitro assessment of P-gp activity, membrane permeability, and unbound fraction are key for CNS drug discovery.
• CSF drug concentration serves as a valuable surrogate for in vivo assessment of CNS exposure.
• Limitations exist in using CSF drug concentration to predict brain exposure, necessitating careful consideration of drug physicochemical properties.