Clinical Pharmacology – Chemical
2019 PharmSci 360
• To predict CNS drug effects, the time dependency and the interrelationships of the processes that govern concentration-time profiles at multiple CNS locations, including the site of action (CNS PK) should be understood
• To that end we need to distinguish between the contribution of CNS characteristics and small-molecule drug properties in governing CNS PK
• As it is the unbound drug that equilibrates over membranes and is able to interact with targets, especially knowledge on unbound extracellular drug concentration-time profiles in different CNS compartments is important.
• The only technique that is able to provide such information is in vivo microdialysis.
• Using microdialysis in human subjects is highly limited, and therefore, we have to rely on preclinical studies
• Microdialysis data are of key value in the development of physiologically based pharmacokinetic (PBPK) modeling, that distinguished between CNS physiological characteristics and drug properties
• With the multi CNS compartment PBPK model that we ultimately developed and validated, we can predict the influence of species (rat, human), influence of transporter functionalities (blocking transporters), time-dependencies , and drug properties on the CNS PK in multiple CNS compartments.