Pharmacogenomics and pharmacometabolomics of levetiracetam in personalized neurotoxicity risk assessment

Levetiracetam (LEV) is one of the most commonly prescribed second-generation antiepileptic drugs due to its selective binding to the synaptic vesicle protein SV2A, predictable pharmacokinetics, minimal drug interactions, and low teratogenic risk. The clinical spectrum of LEV includes focal seizures (as monotherapy or adjunct), and tonic-clonic seizures. Despite its “pharmacokinetic simplicity”, LEV exhibits marked interindividual variability in efficacy and tolerability, primarily due to behavioral and neuropsychiatric adverse drug reactions (ADRs). Less commonly, immune-inflammatory skin, hematologic, hepatic ADRs, and case reports of myotoxic and viscerotoxic reactions occur. The development of LEV-induced ADRs is partially determined by genetic factors (targets/transporters/esterases, vulnerability of monoaminergic networks) and metabolomic shifts (tryptophan-kynurenine pathway, lipid and redox changes), which justifies the application of “omics” approaches for personalized LEV therapy. The review on domestic and international studies (from 2015 to 2025) in the field of LEV-related pharmacogenomics and pharmacometabolomics is presented, aimed at identifying genetic and metabolic biomarkers associated with the risk of neurotoxicity. It demonstrated, that data on SV2A gene and neurotransmitter genes polymorphisms and neurotransmitter genes are still inconsistent. LEV is metabolized by extrahepatic esterases to a pharmacologically inactive compound (L057); no clinically significant reactive LEV metabolites have been identified. The most reproducible pharmacogenetic biomarkers are polymorphisms in the ABCB1 (efflux across the blood-brain barrier) and CES1 (rate of hydrolysis) genes. Pharmacometabolomics confirms the usefulness of assessing the LEV/L057 ratio as an exposure metabolic biomarker. Changes in the tryptophan-kynurenine pathway are primarily experimental, while lipidomic/redox findings are heterogeneous and lack stable clinical validation. Clinically, the risk of neurotoxic behavioral ADRs may be associated with variability in exposure and individual neurobiological vulnerability of neurons to LEV. Personalization of LEV therapy relies on selective therapeutic drug monitoring, assessment of renal function / pregnancy / augmented renal clearance, and modelinformed dosing. However, routine “omics” testing in real clinical practice has not been developed. LEV has a favorable pharmacokinetic profile without the formation of reactive metabolites. The clinical heterogeneity of therapeutic response and ADRs are mainly accounted for by pharmacodynamic and immune-inflammatory mechanisms also involving transporter proteins and esterases. Integration of pharmacogenomics (ABCB1, CES1), targeted pharmacometabolomics (LEV/L057, kynurenine pathway biomarkers), “selective” therapeutic drug monitoring, and model-informed LEV dosing may improve the safety and efficacy of LEV use, creating a realistic framework for personalized epileptology.

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