Application of the LeiCNS-PK model to quantitatively evaluate the roles of BBB active influx and brain metabolism of fluvoxamine and its serotonin transporter (SERT) occupancy in rat and human.

BACKGROUND

Nonlinear brain distribution of fluvoxamine has been attributed to saturable efflux at the blood-brain barrier (BBB). We hypothesize that active BBB influx and brain metabolism jointly govern fluvoxamine brain pharmacokinetics (PK).

METHODS

Rat plasma and brain extracellular fluid (brainECF) PK data were used. The LeiCNS-PK3.5 model was modified by including active BBB influx and brain metabolism (Vmax, Km) of fluvoxamine (LeiCNSPK-3.5-FLV). Plasma PK parameters from observed rat data were used as input for the LeiCNSPK-3.5-FLV. Rat predicted and observed brainECF PK were compared. The model performance was evaluated by graphical diagnostics and quantitative metrics (RAdrug, AFE, AAFE, SMAPE). The rat model was converted to the human version. Using predicted fluvoxamine brainECF PK and a binding kinetic model, rat and human serotonin transporter (SERT) occupancy profiles were predicted.

RESULTS

Combined inclusion of active BBB influx and brain metabolism in LeiCNSPK3.5-FLV accurately predicted the observed brainECF PK data in rats. AUC0-6h of predicted unbound fluvoxamine brainECF PK indicated a dose-dependent contribution of brain metabolism, highlighting its role in capturing the observed nonlinearity across the dosing range investigated. The predicted SERT occupancy in both rats and humans within 2-fold errors in quantitative metrics.

CONCLUSION

Our findings challenge the previously proposed role of active BBB efflux transport in explaining the nonlinear brainECF PK of fluvoxamine. Instead, our findings demonstrate that the combination of active BBB influx and brain metabolism account for fluvoxamine's nonlinear brain kinetics, thereby enabling more accurate mechanistic understanding and improved translational prediction of brainECF PK and SERT engagement.