THE MODEL-AD CONSORTIUM PRECLINICAL TESTING PIPELINE: PHARMACOKINETICS AND PHARMACODYNAMICS OF PROPHYLACTIC TREATMENT WITH LEVETIRACETAM IN THE 5XFAD MOUSE MODEL OF ALZHEIMER’S DISEASE

Abstract

Hyperactive hippocampal excitability has been proposed as a pathophysiological mechanism underlying cognitive impairments in Alzheimer's disease (AD) (Celone et al., 2006). Reduction of hippocampal activity with the antiepileptic drug levetiracetam improves memory task performance in patients with mild cognitive impairment (Bakker et al., 2012); and levetiracetam is currently in clinical trials for the treatment of cognitive impairment associated with AD. As part of the Model Organism Development for Late Onset Alzheimer's Disease (MODEL-AD) consortium, levetiracetam was selected as an initial compound for the establishment of the preclinical drug screening pipeline. In line with the MODEL-AD tiered screening strategy, the pharmacokinetic (PK) profile of leviteracetam was initially evaluated in preparation for pharmacodynamics (PD) assessment using 18F-FDG and 18F-AV45 PET/MRI. Leviteracetam was administered PO (10, 30, and 100 mg/kg) to male and female 5XFAD mice at an age known to demonstrate AD-relevant phenotypic alterations in MR function, memory, and amyloid deposition (6 months; n=3 per sex per dose). Serial blood sampling and terminal plasma and brain tissue were evaluated for exposure levels and a second independent PK study was conducted to refine the optimal dose range and dosing frequency. Leviteracetam produced dose-dependent differences in Cmax, and showed a statistically significant effect of sex. Oral clearance was dose-dependent, and brain concentrations were linearly related with plasma concentrations over a broad range. Mean half-life was 2.7±0.56 hr suggesting no drug accumulation. PK/PD modeling data demonstrated that minimum therapeutic concentrations of levetiracetam will be maintained in plasma and brain at doses as low as 10 mg/kg twice daily. PK analysis of oral levetiracetam in 6 month aged 5XFAD mice, along with PK/PD modeling data, revealed a requirement of twice daily dosing for pharmacodynamic studies. These data have enabled a 3 month prophylactic treatment trial of 5XFAD mice, where the effects of twice daily leviteracetam (10, 30, and 56 mg/kg PO) dosing on 18F-FDG and 18F-AV45 PET/MRI are currently being evaluated.