Purpose: The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy.
Methods: A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine.
Results: Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA = 0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found.
Conclusions: In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.
Keywords: Children; Concentration to dose ratio; Epilepsy; Genetic polymorphisms; Pharmacogenomics; Topiramate; rs4148324.
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