LeiCNS-PK3.2: A physiologically based pharmacokinetic model framework for predicting intracellular concentrations of acyclovir and ganciclovir active metabolites.

BACKGROUND

Effective treatment of viral infections in the central nervous system (CNS) requires adequate nucleoside analogs exposure and conversion into phosphorylated metabolites (TP) in brain cells.

AIM: To develop a CNS PBPK model (LeiCNS-PK3.2) that incorporates active brain cell membrane transport and brain intracellular fluid (brainICF) metabolism to predict and understand target site pharmacokinetics (PK), brainICF active triphosphate (TP) metabolites, and effects of antiviral drugs.

METHOD: LeiCNS-PK3.0 was extended with a brain cell membrane asymmetry factor (AF) using rat-derived Kp,uu,cell values. Intracellular conversion of acyclovir and ganciclovir into TPs was modelled using in vitro kinetic parameters. LeiCNS-PK3.2 was validated on published rat and human plasma, brain extracellular fluid (brainECF), and cerebrospinal fluid (CSF) data. Simulated PK profiles for parent drug standard dosing regimens (acyclovir 10 mg/kg t.i.d.; ganciclovir 5 mg/kg b.i.d.) were compared to parent-drug profiles in brainECF, and TP metabolite in brainICF. Sensitivity analyses were performed on CNS physiological parameters and Kp,uu,cell values.

RESULTS

LeiCNS-PK3.2 accurately recaptured the observed data (<2-fold error range). Simulated brainECF parent drug concentrations often remained below reported IC50 values, whereas brainICF TPs had smaller AUCs and longer time to equilibrium compared to acyclovir/ganciclovir in brainECF. Simulated pathological variations during CNS infection showed minimal impact on brainICF TP exposure, with proportional shifts in brainICF TP concentrations when varying Kp,uu,cell.

CONCLUSIONS

LeiCNS-PK3.2 can predict CNS target-site exposure of TPs and demonstrates that brainECF acyclovir/ganciclovir concentrations are distinct from brainICF TP levels. It may support intracellular PK/PD target determination to optimize dosing strategies for CNS viral infections.