Intravenous diazepam application in a departmental convulsive status epilepticus protocol with CYP2C19 polymorphisms: a pediatric prospective cohort study.

Abstract

Background: Individual variability of therapeutic response and adverse effects of diazepam is frequently observed in pediatric cohorts. It might be related to the genetic polymorphisms in cytochrome P450 2C19 (CYP2C19), a principal enzyme mediating diazepam metabolism.

Objectives: To investigate the association between CYP2C19*2 (c.681G > A), CYP2C19*3 (c.636G > A), and CYP2C19*17 (-806 C > T) polymorphisms and clinical outcomes-specifically treatment efficacy and respiratory adverse effects-following intravenous diazepam administration in children with seizures.

Methods: This prospective, single-center cohort study enrolled 100 pediatric patients (0-18 years) treated with IV diazepam for febrile/afebrile seizures. Genetic analysis was performed using next-generation sequencing. Clinical endpoints included seizure control following one or two diazepam doses and the incidence of respiratory complications. Statistical analyses assessed associations between CYP2C19 genotypes and seizure control outcomes.

Results: The median age was 4.5 years (IQR: 2.4-8.5); 61% were male. Overall, seizure cessation was achieved in 76% with the first dose of IV diazepam and in 79% cumulatively. Respiratory side effects were observed in 15% of patients, with 9% requiring positive pressure ventilation. The CYP2C19*2 and CYP2C19*17 alleles were identified in 19% and 49% of participants, respectively. However, the CYP2C19*3 variant was absent. Notably, the presence of the CYP2C19*17 CT/TT genotype-particularly in combination with the CYP2C19*2 GG genotype-was significantly associated with both diazepam treatment failure (p = 0.038) and increased risk of respiratory adverse effects (p = 0.005).

Conclusion: This study is the first to delineate the clinical relevance of CYP2C19 polymorphisms in a Turkish pediatric population treated with diazepam. The findings underscore the potential utility of pharmacogenetic profiling to predict therapeutic response and enhance the safety of benzodiazepine use in pediatric seizure management.