Enhancing ketamine translational pharmacology via receptor occupancy normalization

Ketamine is used preclinically and clinically to study schizophrenia and depression. Accordingly, it is imperative to understand the temporal relationship between the central concentrations and N-methyl-d-aspartate receptor (NMDAR) interactions of both ketamine and norketamine, its primary active metabolite, across species to assess the translatability of animal models to humans and the back-translation of clinical observations to the preclinical realm. However, such an interspecies normalization of ketamine and norketamine exposures at different clinical and preclinical doses (and their different routes and regimens) is lacking. This work defines the NMDAR occupancy (RO) time course following single doses of ketamine in rats, nonhuman primates (nhp) and humans to allow direct interspecies comparisons of specific ketamine-mediated pharmacodynamics via RO normalization. Total plasma concentration (Cp)-time profiles of ketamine and norketamine were generated from rats and nhp following a single, memory-impairing dose of ketamine; neuropharmacokinetics were determined in rats. [(3)H]MK-801-displacement studies in rats determined estimated mean (95% confidence interval) unbound plasma concentrations (Cp,u) for ketamine and norketamine producing 50% RO (IC50) of 1420 (990, 2140) nM and 9110 (5870, 13700) nM, respectively. Together, these datasets transformed Cp,u-time data to predicted RO (ROpred)-time profiles for rats, nhp and humans at behaviorally relevant ketamine doses. Subsequently, this approach helped determine an infusion paradigm in rats producing a ROpred-time profile mirroring that for a clinically antidepressant infusion. The described indication-independent methodology allows normalization to RO at any time following any ketamine dose (regardless of route or regimen) in any species by simply quantifying the Cp of ketamine and norketamine. Matching temporal RO relationships in animals and humans should allow direct comparisons of specific ketamine-dependent NMDAR-based pharmacodynamics.