Clinically relevant steady‐state plasma levels of serotonin reuptake inhibitors are predicted by pharmacokinetic/pharmacodynamic modelling in mice

Abstract

The purpose of the present investigation is to characterize a pharmacokinetic/pharmacodynamic model in mice for predicting clinically-relevant steady-state concentrations (Css) of the antidepressants escitalopram (ESC), paroxetine (PAR) and sertraline (SRL) in serum/plasma. The time-course of serum and brain drug content, cortical serotonin transporter (SERT) occupancy and 5-hydroxytryptamine-potentiated behavioral syndrome were measured. All drugs produced dose-related increases in serum concentrations and behavioral effects. At non-steady-state conditions, some hysteresis was observed between changes in serum levels of drug and occupancy or behavioral response. An effect-compartment model was applied to collapse hysteresis and predict the steady-state relationship between drug exposure and PD response. The EC20 (PAR, SRL) or EC40 (ESC) for antidepressant-like in vivo efficacy in mice aligned with 80% SERT occupancy. The predicted Css for ESC, PAR and SRL at 80% SERT occupancy in mice are 18 ng/ml, 19 ng/ml and 25 ng/ml, respectively. Clinically effective SERT occupancy by ESC, PAR and SRL in depressed patients is approximately 80%, and the corresponding plasma Css are 10–31 ng/ml, 21–95 ng/ml and 20–48 ng/ml, respectively. Thus, modelling the time-course of the PK/PD effects of a single drug administration in mice can be used to predict therapeutically-relevant plasma Css. Funding by H. Lundbeck A/S.