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Cited by 16Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study

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Onos, Kristen D., Quinney, Sara K., Jones, David R., Masters, Andrea R., Pandey, Ravi, Keezer, Kelly J., Biesdorf, Carla, Metzger, Ingrid F. +15 more·2022·Alzheimer's & Dementia: Translational Research & Clinical Interventions
DOI 10.1002/trc2.12329PMC PMC9398229
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Abstract

Introduction: Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti‐seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease Preclinical Testing Core. Methods: A multi‐tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results: Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC 0‐∞ , and CL/F, and a dose dependence in AUC 0‐∞ . After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18 F‐AV45, and 18 F‐fluorodeoxyglucose ( 18 F‐FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug‐ and dose‐related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18 F‐FDG uptake. Discussion: This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non‐linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post‐treatment gene expression analysis demonstrated LEV dose‐related changes in immune function and neuronal‐signaling pathways relevant to human AD, and aligned with regional 18 F‐FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights: Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice. Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic. Drug‐ and dose‐related differences in gene expression relevant to human brain regions and pathways were also similar to brain region–specific changes in 18F‐fluorodeoxyglucose uptake.

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  • Our list of core genes can be interpreted as robust tau-responsive genes for future study.

    “As preclinical studies continue to make direct comparisons between human and mouse transcriptomics (Monzón-Sandoval et al., 2022; Onos et al., 2022), our list of core genes can be interpreted as robust tau-responsive genes for future study.”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Onos et al., 2022

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Authors
Onos, K. D., Quinney, S. K., Jones, D. R., Masters, A. R., Pandey, R., Keezer, K. J., Biesdorf, C., Metzger, I. F., Meyers, J. A., Peters, J., Persohn, S. C., McCarthy, B. P., Bedwell, A. A., Figueiredo, L. L., Cope, Z. A., Sasner, M., Howell, G. R., Williams, H. M., Oblak, A. L., Lamb, B. T., Carter, G. W., Rizzo, S. J. S., & Territo, P. R.
Affiliations
  • Jackson Laboratory (US)
  • Indiana University School of Medicine (US)
  • Indiana University School of Medicine Indianapolis Indiana USA
  • University of Pittsburgh (US)
Corresponding author
Onos, Kristen D.
ORCID
Venue
Alzheimer's & Dementia: Translational Research & Clinical Interventions
Publisher
Wiley
Published
2022-01
Volume
8
Issue
1
Pages
e12329-e12329
ISSN
2352-8737 (ISSN-L)
DOI
10.1002/trc2.12329
PMC
PMC9398229
OpenAlex
W4292772515
Cited by
16
References
3
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 1
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • Mayo Foundation for Medical Education and Research (AG016574)
  • Arizona Department of Health Services (P30 AG19610, P50 AG016574, U24 NS072026, 05-901, 211002, R01 AG032990)
  • CurePSP
  • Rush University
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, U24 NS072026, 211002)
  • Melvin and Bren Simon Cancer Center, Indiana University
  • National Institute on Aging (211002, R01AG017917, U01-AG006576, P30-AG 10161, P30-AG-19610, R01‐AG17917, R01 AG003949, R01 AG15819, AG046139, R01-AG36836, R01AG018023, AG016574, R01AG036836, AG-19610, U01AG006786, P01AG003949, AG-006786, R01-AG025711, R01AG015819, P30AG010161, P50AG025711, AG025711, R01AG032990, P30AG019610, 05-901, P01AG017216, U01AG046139, R21AG067923, AG017216, AG003949, U54AG065187, U54AG054345, R01-AG017216, P50AG016574)
  • National Institute of Neurological Disorders and Stroke (R01NS080820, NS072026, 211002, NS080820, U24NS072026, 05-901, P30 AG19610)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, 5xFAD mice, pharmacokinetics/pharmacodynamics, sex differences, dose dependence, nonlinear kinetics, 18F-FDG PET, brain glucose metabolism, gene expression changes, immune function, neuronal signaling, cognitive function, epilepsy, preclinical to clinical translation

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