Pharmacokinetic/pharmacodynamic feedback modelling of the functional corticosterone response in rats after acute treatment with escitalopram.
The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the drug-induced corticosterone response after administration of escitalopram in rats. To achieve this, a mechanistic feedback turnover model mimicking the acute mechanism of action of selective serotonin reuptake inhibitors was assessed. Conscious and freely moving rats received constant rate infusions of 2.5, 5 or 10 mg/kg escitalopram or vehicle over 60 min. Automated serial blood sampling was conducted to determine escitalopram and corticosterone concentrations. The PK/PD model consisted of a turnover model of escitalopram-evoked changes in response, which included an inhibitory feedback moderator function. Accordingly, response acted linearly on the production (k(tol)) of the moderator, which acted inversely on the production (k(in)) of response. The escitalopram plasma kinetics served as input to an inhibitory function acting on the loss (k(out)) of response. The corticosterone responses were successfully described using the model by fitting responses from all doses simultaneously resulting in estimation of drug parameters (I(max), IC(50) and n) in addition to system parameters (k(in), k(out) and k(tol)) for the whole exposure range. Thus, the applicability of the model for analysis of the acute selective serotonin reuptake inhibitor-induced corticosterone response including acute auto-inhibitory feedback was demonstrated.
Bundgaard
Christoffer
C
Discovery ADME, Copenhagen, Denmark. cbun@lundbeck.com
Larsen
Frank
F
Jørgensen
Martin
M
Mørk
Arne
A
D000818:Animals; D015283:Citalopram / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*
D015283:Citalopram; D003345:Corticosterone; D017367:Selective Serotonin Reuptake Inhibitors