Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

Abstract

Background and purpose: Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice. Experimental approach: Serum and whole brain drug concentrations, cortical SERT occupancy and 5-HTP-potentiated behavioral syndrome were measured over 6 h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [ 3H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([ 3H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect-compartment model was applied to collapse the hysteresis and predict the steady-state relationship between drug exposure and PD response. Key results: The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18 ng mL -1, 18 ng mL -1 and 24 ng mL -1, respectively, with corresponding responses in the 5-HTP behavioral model being between 20-40% of the maximum. Conclusions and implications: Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6-21 ng mL -1, 21-95 ng mL -1 and 20-48 ng mL -1 for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5-HTP-potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values. © 2008 Macmillan Publishers Limited All rights reserved.