%0 Journal Article
%T Pharmacogenetic Determinants of Valproic Acid Efficacy, Toxicity, and Serum Levels in Genetic Generalized Epilepsy
%A Joseph Okello
%A Samuel Otieno
%A Peter Mwangi
%J Specialty Journal of Pharmacognosy, Phytochemistry, and Biotechnology
%@ 3062-441X
%D 2024
%V 4
%N 1
%R 10.51847/kdWAPNKD7J
%P 200-210
%X Responses to antiseizure medications (ASM) vary widely from one individual to another, both in terms of benefit and adverse reactions. Genetic differences are believed to play a meaningful role in shaping these outcomes. Valproic acid (VPA), a commonly prescribed ASM, is influenced by numerous pharmacogenetic elements. Yet, unlike agents such as carbamazepine or phenytoin, the amount of evidence linking VPA to specific genetic variants remains limited. This study was therefore designed to investigate how selected pharmacogenetic markers relate to VPA effectiveness, tolerability, and serum levels in a uniform group of newly diagnosed patients with genetic generalized epilepsies (GGE). This prospective cohort project extracted demographic, clinical, and treatment information from the medical charts of individuals with GGE. Whole-exome sequencing was completed in partnership with Epi25. Variants connected to VPA response, biotransformation, or toxicity were gathered from PharmGKB. The subsequent analysis assessed whether these variants showed measurable associations with clinical outcomes during VPA therapy.

Among 166 enrolled participants, 60 (36.1%) did not respond adequately to treatment, whereas 106 (63.9%) showed successful outcomes. After adjusting for the VPA maintenance dose, carriers of the rs3892097 variant (CYP2D6) demonstrated a 2.5-fold higher probability of treatment failure compared with noncarriers (p = 0.026). The rs1057910 allele (CYP2C9*3) was linked to higher circulating VPA concentrations (p = 0.034). The rs1137101 variant (LEPR, a regulator of metabolic processes) was tied to an increased likelihood of weight gain (coefficient 3.430 [0.674; 6.186], p = 0.015) as well as more frequent hair loss (OR = 3.394 [1.157; 9.956], p = 0.026). In contrast, rs4480 in SOD2, which encodes a mitochondrial antioxidant enzyme, corresponded to a reduced rate of hair loss (OR = 0.276 [0.089; 0.858], p = 0.026). The results emphasize that inherited genetic variation contributes meaningfully to differences in VPA treatment outcomes and point toward the value of developing individualized therapeutic strategies aimed at improving efficacy and reducing adverse effects.
%U https://galaxypub.co/article/pharmacogenetic-determinants-of-valproic-acid-efficacy-toxicity-and-serum-levels-in-genetic-genera-efk7llfdn1rqjay