CYP2C9 Pharmacogenetic Variants and Adverse Drug Reactions to Antiseizure Medications: An Exploratory Analysis in the Venezuelan Andes
Alexis Morales-Ortiz, Luis Abel Quiñones, Sol Betzabeth Rondón-Simancas, Gustavo Paredes, Andrea Avendaño, Zaida Gonzalez, Haydee Chávez, Juan J. Palomino-Jhong, María R. Bendezú, Jorge A. García, Elizabeth J. Melgar-Merino, Pompeyo A. Cuba-Garcia, Doris Laos-Anchante, Paulina Eliades Yarasca-Carlos, José Santiago Almeida-Galindo, Ricardo Pariona-Llanos, Felipe L. Ignacio-Cconchoy, Alvaro E. Maguiña-Ignacio, Berta Loja-Herrera, Richard Yaya-Araujo, Nelson M. Varela, Angel T. AlvaradoEpilepsy is a chronic neurological disorder with a high global prevalence. In Venezuela, the limited availability of epidemiological and pharmacogenetic data represents an important public health challenge. Antiseizure medications (ASMs) are frequently associated with adverse drug reactions (ADRs), which may be influenced by genetic variability in drug-metabolising enzymes. This study evaluated the association between the CYP2C9*2 and CYP2C9*3 variants and the occurrence of ADRs in patients receiving anticonvulsant treatment in the Venezuelan Andes. An observational, analytical, cross-sectional study was conducted in 72 patients. Genomic DNA was extracted from venous blood, and CYP2C9 genotypes were determined by real-time PCR using TaqMan® probes. The frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 0.15 and 0.06, respectively. The metaboliser phenotype was significantly associated with the presence of ADRs. The risk of ADRs was elevated in the intermediate/poor metaboliser group (IM/PM: OR = 17.45; 95%CI: 5.09–76.56; p < 0.001) and in patients on polypharmacy (OR = 15.03; 95%CI: 2.73–157.37; p = 0.001), although this latter estimate showed marked imprecision due to the width of its interval. Consistent with this, the ADR rate was higher in PM (100%; 3/3) and IM (84.2%; 16/19) than in normal group (20.9%; 9/43). In the monotherapy subgroup, the type of ASM showed no association with the occurrence of ADR (p = 0.741). Among normal metabolisers receiving polytherapy, regimens containing valproic acid were associated with the highest proportion of ADRs, with dual therapy including lamotrigine accounting for 28.57%. Although the overall analysis indicated differences in ADR occurrence according to polytherapy regimen (p = 0.043), the limited sample size restricts the strength of these findings. These results suggest that CYP2C9*2 and CYP2C9*3 variants may contribute to variability in the safety of anticonvulsant treatment among patients from the Venezuelan Andes by influencing CYP2C9 metaboliser phenotypes, and consequently, drug pharmacokinetics. Further studies in larger and more representative Venezuelan populations are warranted to validate these findings.