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


METHODS
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.


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
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.
Discovery ADME, H Lundbeck A/S, Valby, Denmark. makr@lundbeck.com
M
M
Kreilgaard
D G
DG
Smith
L T
LT
Brennum
C
C
Sánchez
D000818:Animals; D015283:Citalopram / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008954:Models, Biological; D017374:Paroxetine / Q000493:pharmacokinetics / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D020280:Sertraline / Q000493:pharmacokinetics / Q000494:pharmacology
D015283:Citalopram; D017374:Paroxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline