PHARMACOLOGICAL VALIDATION OF NEUROKIT AS A PORTABLE, SENSITIVE AND REPRODUCIBLE TEST BATTERY IN EARLY CLINICAL CENTRAL NERVOUS SYSTEM (CNS) DRUG DEVELOPMENT

Background

NeuroKit has been developed as a portable equivalent to NeuroCart, a well-established and validated test battery that quantifies a wide range of pharmacodynamic (PD) CNS effects in early drug development. NeuroKit incorporates CNS domains previously demonstrated to be informative in early phase clinical trials using NeuroCart: saccadic eye movements (arousal), adaptive tracking (visuomotor coordination, sustained attention), finger tapping (fine motor performance; visuomotor coordination), smooth pursuit (visuomotor coordination), body sway (postural balance), N-back (working memory), VAS Bond and Lader and VAS Bowdle (subjective drug effects). The present study aimed to pharmacologically validate NeuroKit against NeuroCart using three CNS-penetrant compounds with distinct, wellknown mechanisms of action, establishing its sensitivity and reproducibility in capturing PD effects in humans compared to NeuroCart in early-phase clinical pharmacology studies.

Methods

In this randomized , double-blind, double-dummy, placebo-controlled, four-way crossover study, 16 healthy male and female participants received single dose of a non-selective GABA-A receptor agonist (lorazepam 2 mg PO), a dopamine reuptake inhibitor and releaser (modafinil 200 mg PO), a NMDA receptor antagonist (S-ketamine IV 0.475 mg/kg for 75 min + 0.275 mg/kg for 75 min) and placebo. NeuroKit and NeuroCart were administered predose, and counterbalanced at five postdose timepoints in each treatment period to account for potential order effects. PD endpoints were analyzed using linear mixed-effects models. Least-squares mean (LSM) and Minimal Detectable Effects (MDE) contrasts were used to estimate treatmentplacebo differences for NeuroKit versus NeuroCart and to compare sensitivity to treatment effects between methods. NeuroKit reproducibility was assessed using F-test for inter-and intraparticipant variance.

Results

NeuroKit detected treatment effects consistent with NeuroCart in 88% of the endpointdrug contrasts. Although statistical significance was not observed in the remaining cases, direction and magnitude of treatment effects were consistent across methods. Furthermore, for the most informative endpoints - saccadic peak velocity, adaptive tracking and body sway-significant effects were detected by both NeuroCart and NeuroKit. MDEs were comparable across endpoints, reflecting similar sensitivity between methods. MDEs were lower or equal for NeuroKit than for NeuroCart in 55% of endpoints, including those covering the most relevant CNS domains, while those for NeuroKit were slightly higher than for NeuroCart for psychomotor function. Inter-and intra-participant variance did not differ significantly across all endpoints between both NeuroKit and NeuroCart, reflecting reproducibility.

Conclusions

NeuroKit detected CNS effects consistent with the mechanisms of action of lorazepam, modafinil and S-ketamine, and comparable to the PD profiles previously demonstrated for these compounds using NeuroCart. Furthermore, NeuroKit demonstrated pharmacological sensitivity and reproducibility when benchmarked against NeuroCart. Together these data support the use of NeuroKit in early-phase clinical studies with CNS-active compounds.