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

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.