Quantification of the Drug Effect and Exploration of Mechanism of Action of Two NMDA Channel Blockers, AZD6765 and Ketamine, using Mouse EEG Data
Carin Wallsten(1), Oliver Ackaert(2), Petra Ekerot(1), Nelleke Snelder(2), Mike Quirk(3), Carlos Fonck(4), and Bart Ploeger(1)
(1)Modelling & Simulation, CNSP iMed, AstraZeneca R&D Södertälje, Sweden; (2)LAP&P Consultants BV, Leiden, The Netherlands; (3)CNSP iMed, AstraZeneca R&D, Wilmington, Delaware, USA; (4)Safety Assessment US, AstraZeneca R&D, Wilmington, Delaware, USA
Objectives: AZD6765 and ketamine are NMDA channel blockers, which differ in how they interact with the NMDA channel. Ketamine has shown effects in major depressive disorder (MDD) [1] and AZD6765 is under clinical development for MDD. A therapeutic hypothesis is that NMDA channel blockers normalize aberrant electrical activity in key depression-associated brain networks. Change in the EEG amplitude within the gamma frequency band is a potential pharmacodynamic biomarker of NMDA antagonist-mediated cortical disinhibition. Our first objective was to estimate the potency and efficacy of AZD6765 and ketamine, using the change in gamma EEG, and secondly to explore if the degree of trapping in the NMDA ion channel (AZD6765 is a low and ketamine a high trapping compound) affects the underlying mechanism of action on the gamma EEG.
Methods: The EEG was recorded in mice for 5 single doses of each of the compounds (30 min baseline and 90 min postdose recording in 2 min bins) and the data analyzed using a population approach. The PK of the compounds was obtained from satellite animals and estimated population PK parameters were used as input for the analysis of the time-course of the drug effects in the EEG studies.
Results: Both AZD6765 and ketamine increased the gamma EEG with increasing plasma concentration. For AZD6765, the delay between the change in plasma concentration and gamma EEG was best described with a turnover model with inhibition of the turnover rate, using a sigmoidal Emax model. In addition, a negative moderator feedback mechanism was identified. The ketamine data could not be described assuming an inhibition of the turnover rate, but were best described using a direct and delayed effect, using a turnover model with stimulation of the production of the EEG signal.
Conclusions: In this study, ketamine caused a greater increase in gamma EEG than did AZD6765. PK-PD modeling of the gamma EEG showed some differences between the compounds, which may be related to a difference in mechanism of action and different degree of trapping in the NMDA channel. This hypothesis warrants further investigation.
References:
[1] Zarate CA, et al. A randomized trial of a N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006:63:856-64
