Prediction of Human Serotonin and Norepinephrine Transporter Occupancy of Duloxetine by Pharmacokinetic/Pharmacodynamic Modeling in the Rat

Abstract

Translation of central nervous system occupancy and clinical effect from animal models to humans has remained elusive for many pharmacological targets. The current studies evaluate the ability of a rodent pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to translate ex vivo occupancy determined in rats to that observed after positron emission tomography (PET) imaging in humans for the dual serotonin transporter (SERT) and norepinephrine transporter (NET) inhibitor duloxetine. Ex vivo transporter occupancy in rat spinal cord was evaluated after single oral doses of 0.3 to 60 mg/kg. A novel methodology, based on the initial rates of association of transporter selective radioligands to tissue homogenates, was developed and validated for the assessment of ex vivo transporter occupancy. Duloxetine exhibited selectivity for occupancy of SERT over NET in rat spinal cord with ED 50 values of 1 and 9 mg/kg, respectively. Corresponding EC 50 values for the inhibition of SERT and NET based on unbound duloxetine spinal cord concentrations were 0.5 and 8 nM. An effect compartment PK/PD modeling approach was used to analyze the relationship between the time course of duloxetine plasma concentration and SERT and NET occupancy. Duloxetine inhibited SERT and NET in rat spinal cord with a plasma EC 50 of 2.95 and 59.0 ng/ml, respectively. Similar plasma EC 50 values for the inhibition of SERT (2.29 -3.7 ng/ml) have been reported from human PET studies. This study illustrates the value of translational PK/PD modeling approaches and suggests that the preclinical modeling approach used in the current study is capable of predicting plasma concentrations associated with 50% occupancy of SERT in the human central nervous system.

Translation of Central Nervous System Occupancy from Animal Models: Application of Pharmacokinetic/Pharmacodynamic Modeling

“…Although the authors concluded that the estimates of duloxetine sensitivity parameter were similar, the estimated EC 50 in humans was significantly higher than that observed in rats. The mean estimate of EC 50 reported by Takano et al (2006) in humans was 60% higher (3.70 ng/ml) than the mean estimates in humans reported by Abanades et al (2011) (2.29 ng/ml), and in rats reported by Bourdet et al (2012) (2.32 ng/ml). These differences appear to be a consequence of an inconsistent approach to data analysis and PK/PD modeling assumptions between the three reports.…”

“…The authors provided a strong foundation supporting the hypothesis that occupancy of SERT by duloxetine is a translatable biomarker between rats and humans while emphasizing the value of translational PK/PD modeling approaches. Bourdet et al (2012) compared the parameter estimates from their modeling efforts of SERT occupancy in rats to those reported for humans in two literature reports (Takano et al, 2006;Abanades et al, 2011). Although the authors concluded that the estimates of duloxetine sensitivity parameter were similar, the estimated EC 50 in humans was significantly higher than that observed in rats.…”

“…Despite the fact that the site of action in humans is still unclear, the analgesic effects are probably attributed to SERT inhibition located both spinally and supraspinally (Iyengar et al, 2004;Mixcoatl-Zecuatl and Jolivalt, 2011). Bourdet et al (2012) reported the translation of CNS receptor occupancy from animals to humans using PK/PD modeling. The group suggested that the preclinical modeling approach was capable of predicting EC 50 occupancy of SERT in the human CNS.…”

“…Although a simple Hill model was used in all three reports to describe SERT occupancy data, Takano et al (2006) assumed a maximal achievable SERT occupancy (E max ) of 100%. In comparison, Abanades et al (2011) and Bourdet et al (2012) estimated the maximal SERT occupancy in humans and rats, respectively. The mean estimates of E max were 84.0 and 85.6% in humans and rats, respectively.…”

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

“…From various receptor occupancy, PET imaging studies with clinically approved antidepressants in humans, it has been established that an occupancy of 70-80% is required for the SERT and 50-70% is required for the NET for production of an antidepressant effect [153,[158][159][160]. Also it has been established that to produce a dopamine effect without producing any addiction liability, an occupancy of 30-40% is required for the DAT [161].…”