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Published on: April 1, 2019
UGT1A polymorphism rs4148324 associated with topiramate plasma concentration to dose ratio in children with epilepsy
Shifeng Wei1, Xingmeng Li2, Han Wu1
1Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
Insights
Genetic variations impact topiramate levels in children with epilepsy. Specifically, rs4148324 influences normalized topiramate plasma concentration, aiding personalized treatment strategies.
Area of Science:
- Pharmacogenomics
- Clinical Pharmacology
- Epilepsy Treatment
Background:
- Topiramate is a widely used antiepileptic drug in pediatric populations.
- Individual variability in topiramate response necessitates understanding factors influencing its pharmacokinetics.
- Genetic polymorphisms are potential determinants of drug concentration-to-dose ratios.
Purpose of the Study:
- To investigate the association between specific genetic polymorphisms and the topiramate concentration to dose ratio (CDR) in children with epilepsy.
- To identify genetic markers that predict topiramate plasma concentrations relative to dosage in pediatric patients.
Main Methods:
- A cohort of 163 pediatric epilepsy patients on topiramate therapy was studied.
- Topiramate plasma concentrations were measured using ultra-performance liquid chromatography-tandem mass spectrometry.
- 30 single nucleotide polymorphisms (SNPs) were genotyped, and their association with logarithmic transformed CDR (lnCDR) was analyzed using linear regression.
Main Results:
- The genetic variant rs4148324 (within UGT1A1/3-10) showed a significant association with lnCDR (BETA = 0.182, P = 0.010).
- Individuals with the G allele of rs4148324 exhibited higher normalized topiramate plasma concentrations.
- No other significant associations between the tested SNPs and topiramate lnCDR were identified.
Conclusions:
- The rs4148324 polymorphism is associated with normalized topiramate plasma concentration in pediatric epilepsy patients.
- This finding suggests a potential role for UGT1A variants in topiramate pharmacokinetics.
- Further research is needed to validate these results and explore their clinical implications for topiramate dosing.
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.
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