Table 3.

Comparison of the improved aspects in LeiCNS-PK3.0 versus LeiCN-PK1.0

Aspect	LeiCNS-PK1.0	LeiCNS-PK3.0
pH factor (PHF)	Defined as the ratio of the neutral fraction of a drug of a given compartment to that of plasma	Defined as the neutral fraction of a drug in a given compartment
	Calculated using Henderson-Hasselbalch equations with pH of the compartment, pH of plasma, and the drug-specific ionization constant	Calculated using adapted Henderson-Hasselbalch equations using compartment specific pH and the drug-specific ionization constant
Brain tissue non-specific binding	Using binding factor	Mechanistic description
	Instantaneous	According to diffusion clearance between aqueous and lipid phases
	Binding occurs within the brain ECF to a hypothetical compartment	Binding occurs to the phospholipids of the brain cell membrane
	Relies on total brain-to-plasma concentration ratio (Kp). Kp is calculated using drug lipophilicity (logP), unbound drug fraction in brain (fu,b) and plasma (fu,p), and brain and plasma tissue composition	Relies on drug lipophilicity and the volume of brain phospholipids
Passive paracellular transport	Paracellular route is restricted to neutral drug only	Paracellular route is available for both neutral and charged drug