Pharmacokinetic/Pharmacodynamic Feedback Modelling of the Functional Corticosterone Response in Rats after Acute Treatment with Escitalopram

Abstract: 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, IC₅₀ 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.