CYP2C19 genotype and sodium channel blockers in lacosamide-treated children with epilepsy: two major determinants of trough lacosamide concentration or clinical response

Abstract

Background: The widespread clinical use of lacosamide (LCM) has revealed significant individual differences in clinical response, with various reported influencing factors. However, it remains unclear how genetic factors related to the disposition and clinical response of LCM, as well as drug-drug interactions (DDIs), exert their influence on pediatric patients with epilepsy.

Objectives: To evaluate the impact of genetic variations and DDIs on plasma LCM concentrations and clinical response.

Design: Patients with epilepsy treated with LCM from June 2021 to March 2023 in the Children's Hospital of Nanjing Medical University were included in the analysis.

Methods: The demographic information and laboratory examination data were obtained from the hospital information system. For the pharmacogenetic study, the left-over blood specimens, collected for routine plasma LCM concentration monitoring, were used to perform genotyping analysis for the selected 26 single nucleotide polymorphisms from 14 genes. The trough concentration/daily dose (C ₀/D) ratio and efficacy outcomes were compared.

Results: Patients achieved 90.1% and 68.9% responder rates in LCM mono- and add-on therapy, respectively. The genetic variant in the CYP2C19 *2 (rs4244285) was associated with a better responsive treatment outcome (odds ratio: 1.82; 95% confidence interval: 1.05-3.15; p = 0.031). In monotherapy, 36% of patients were CYP2C19 normal metabolizers (NMs), 49% were intermediate metabolizers (IMs), and 15% were poor metabolizers (PMs) carrying CYP2C19 *2 or *3. Of note, the C ₀/D ratios of IMs and PMs were 9.1% and 39.6% higher than those of NMs, respectively. Similar results were in the add-on therapy group, and we also observed a substantial decrease in the C ₀/D ratio when patients were concomitant with sodium channel blockers (SCBs).

Conclusion: This study was the first to confirm that CYP2C19 *2 or *3 variants impact the disposition and treatment response of LCM in children with epilepsy. Moreover, concomitant with SCBs, particularly oxcarbazepine, also decreased plasma LCM concentration.

Keywords: CYP2C19; children; focal epilepsy; lacosamide; therapeutic drug monitoring.

Figure 1.

Kaplan–Meier survival estimates for probability to remain responders. (a) In 292 patients (median survival time: 37 months). (b) Divided into monotherapy and add-on therapy groups.

Figure 2.

Plasma LCM concentrations and responder rate between low dose, medium dose, and high dose groups. LCM, lacosamide.

Figure 3.

Comparison of LCM concentrations between responders and nonresponders, stratified by the CYP2C19 *2 genotype. **p < 0.01. LCM, lacosamide.

Figure 4.

Comparison of LCM concentrations between responders and nonresponders, divided into monotherapy and add-on therapy. LCM, lacosamide.

Figure 5.

Frequencies of CYP2C19 genotypes, phenotypes, and plasma LCM concentrations by therapeutic group: subtherapeutic (<2 μg/mL), therapeutic (2–7 μg/mL), or supratherapeutic range (>7 μg/mL).

Figure 6.

C₀/D ratio ((µg/mL)/mg) of LCM in three CYP2C19 phenotypes groups. (a) In monotherapy. (b) In add-on therapy. (c, d) A comparison of C₀/D ratio between monotherapy and coadministration with SCB agents and non-SCB medications. *p < 0.05.**p < 0.01. ***p < 0.001. LCM, lacosamide; SCB, sodium channel blocking.

Figure 7.

A comparison of C₀/D ratio ((µg/mL)/mg) between different CYP2C19 genotypes (*1, *2, or *3) in LCM monotherapy. ***p < 0.001. LCM, lacosamide.