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The blood-brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration-time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brain ECF ) and intracellular fluid (brain ICF ) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (para radius ), brain ECF volume, and pH of brain ECF (pH ECF ) and of brain ICF (pH ICF ) on brain ECF and brain ICF PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brain ECF and brain ICF PK. Altered para radius , pH ECF , and pH ICF affected both the rate and extent of BBB drug transport, whereas changes in CBF and brain ECF volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brain ECF and brain ICF target site PK.

Impact of CNS Diseases on Drug Delivery to Brain Extracellular and Intracellular Target Sites in Human: A “WHAT-IF” Simulation Study