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. [(3)H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([(3)H]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.

Figure 1

Semilogarithmic plot of mean (±s.e.mean) serum concentration–time profiles of (a) escitalopram, (b) paroxetine and (c) sertraline following s.c. administration in mice.

Figure 2

Time course of the effects of (a) escitalopram, (b) paroxetine and (c) sertraline administered s.c. on 5-HTP-potentiated behaviours in mice. Data represent the mean (±s.e.mean) for 8–16 mice per group. 5-HTP, 5-hydroxytryptophan.

Figure 3

Time profile of mean (±s.e.mean) brain and serum concentrations, SERT occupancy and 5-HTP-potentiated syndrome score following (a) escitalopram (1.0 mg kg⁻¹, s.c.), (b) paroxetine (0.27 mg kg⁻¹, s.c.) or (c) sertraline (2.2 mg kg⁻¹, s.c.) administration in mice. Data are drug concentration in ng g⁻¹ (brain) or ng mL⁻¹ (serum), or percent response (5-HTP, occupancy). 5-HTP, 5-hydroxytryptophan; SERT, serotonin transporter.

Figure 4

Plot of the relationship between serum concentration and 5-HTP-potentiated syndrome score at individual time points in mice following the s.c. administration of (a) escitalopram (1.0 mg kg⁻¹, s.c.), (b) paroxetine (0.27 mg kg⁻¹, s.c.) or (c) sertraline (2.2 mg kg⁻¹, s.c.). The hysteresis of non-steady-state raw data (Raw) is shown, as well as the results representing predicted steady-state relationship following collapse (Collapsed) with an effect-compartment model (escitalopram and paroxetine: k_e0=5 h⁻¹; sertraline: k_e0=0.8 h⁻¹). 5-HTP, 5-hydroxytryptophan.

Figure 5

Predicted (pred) steady-state pharmacodynamic relationship between cortical SERT occupancy (Occ) and 5-HTP-potentiated syndrome score (5-HTP) in the mouse for (a) escitalopram, (b) paroxetine and (c) sertraline. Symbols are observed (obs) response values at predicted steady-state serum concentrations (Css), and the lines are modelled curves to the data using a sigmoidal E_max model. The shaded area represents the range of clinically observed serum concentrations. 5-HTP, 5-hydroxytryptophan; SERT, serotonin transporter.