Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine.

Marcel M Van Gaalen,Chandrali Bhattacharya,Saugat Adhikari,Christina Schlumbohm,Joost H Folgering,Douglas Steinbach,Robert E Stratford

doi:10.1124/jpet.118.254508

Marcel M Van Gaalen, Chandrali Bhattacharya + Show 5 more

Open Access

https://doi.org/10.1124/jpet.118.254508

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Abstract

Acute central nervous system exposure to dextroamphetamine (d-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semimechanistic pharmacokinetic and pharmacodynamic (PK/PD) model with consideration of these multiple effects as a basis was developed. Integrated pharmacokinetics of d-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid were characterized using a population approach. This PK model was then linked to an indirect-response pharmacodynamic model using as a basis the measurement of extracellular striatal dopamine, also via microdialysis. In both rats and nonhuman primates (NHPs), d-amphetamine stimulation of dopamine outflow (reverse transport) through DAT was primarily responsible for the dose-linear increase in dopamine. As well, in both species a moderator function was needed to account for loss of the dopamine response in the presence of a relatively sustained d-amphetamine ECF exposure, presumptive of an acute tolerance response. PK/PD model structure was consistent between species; however, there was a 10-fold faster return to baseline dopamine in NHPs in response to an acute d-amphetamine challenge. These results suggest preservation from rodents to NHPs regarding the mechanism by which amphetamine increases extracellular dopamine, but a faster system response in NHPs to tolerate this increase. This microdialysis-based PK/PD model suggests greater value in directing preclinical discovery of novel approaches that modify reverse transport stimulation to treat amphetamine abuse. General value regarding insertion of an NHP model in paradigm rodent-to-human translational research is also suggested.

Highlights

Abuse of amphetamine-type stimulants (D-amphetamine, methamphetamine, and ecstasy) is a major public health threat worldwide (Krasnova and Cadet, 2009; Perez-Mana et al, 2013)
Chemicals used in the preparation of intravenous formulation, microdialysis perfusion buffer, and solvents used for high-performance liquid chromatography–tandem mass spectrometry (MS/MS) analyses were of reagent grade, indicating that they conform to specifications defined by the Committee on Analytical Reagents of the American Chemical Society
The goal of this work was to define a PD model using as a basis a consideration of the multiple pathways by which D-amphetamine increases dopamine levels in the striatum (Hutson et al, 2014), and the negative feedback pathways employed to limit this increase (Schmitt and Reith, 2010)

Summary

Introduction

Abuse of amphetamine-type stimulants (D-amphetamine, methamphetamine, and ecstasy) is a major public health threat worldwide (Krasnova and Cadet, 2009; Perez-Mana et al, 2013). Given its importance in regulating dopamine-elicited behaviors, DAT function itself is subject to negative feedback regulation This regulation has been shown to proceed via a kinase-dependent signaling cascade that couples DAT expression to the dopamine D2 autoreceptor (D2R) (Chen et al, 2013). Activation of the D2R increases DAT reuptake capacity by trafficking presynaptic terminal stores of DAT to the synaptic membranes of dopamine neurons (Bolan et al, 2007; Eriksen et al, 2010). This increased capacity to remove dopamine from synapses limits postsynaptic dopamine-elicited effects

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