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

Abstract

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.

Keywords: CNS diseases; blood–brain barrier; brain pharmacokinetics; passive transport.

Figure 1

LeiCNS-PK3.0 model structure. The central nervous system (CNS) model connects to the plasma via cerebral blood flow. LeiCNS-PK3.0 accounts for the brain and cerebrospinal fluid (CSF) compartments, the presence of the blood–brain barrier (BBB) and blood–CSF barriers, drug transport across the barriers and within the CNS, and physiological process such as non-specific binding and the effect of pH on drug ionization and on its passive transport.

Figure 2

Simulated concentration–time profiles of selected drugs at physiological and pathophysiological values of CBF, tight junction paracellular pore radius (para_radius), brain_ECF volume, pH_ECF, and pH_ICF. Para_radius affected the rate and extent of passive drug transport across the BBB, pH_ECF and pH_ICF affected the brain_ECF and brain_ICF unbound drug concentration-time profile (PK), whereas cerebral blood flow and brain_ECF volume had a very modest (if any) effect. The fixed plasma PK used excludes the involvement of plasma PK in the observed changes.

Figure 3

Heatmaps summarizing the effect of pathophysiological changes of CBF, tight junction paracellular pore radius (para_radius), brain_ECF volume, pH_ECF, and pH_ICF on brain pharmacokinetic parameters: C_max, T_max, AUC, Kp_uu,ECF, and Kp_uu,cell. C_max and T_max define the rate of BBB drug transport, while AUC and Kp_uu define the extent of drug transport. Effect of pathophysiological changes remain drug (class) specific. Similar to the concentration–time profiles, para_radius, pH_ECF, and pH_ICF had a profound effect on brain pharmacokinetics compared to the minor effect of cerebral blood flow and brain_ECF volume. The fixed plasma PK used excludes the involvement of plasma PK in the observed changes.