Abstract：
OBJECTIVE: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy.
METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up.
RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ± 328.1 ng/mL, in contrast to the CC phenotype at 334.0 ± 161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy.
CONCLUSIONS: The CYP3A4×10 gene\'s genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.
METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up.
RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ± 328.1 ng/mL, in contrast to the CC phenotype at 334.0 ± 161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy.
CONCLUSIONS: The CYP3A4×10 gene\'s genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.
摘要：
目的：本研究首次评估CYP3A4基因多态性对中国小儿癫痫患者血药浓度和有效性的影响。
方法：我们招募了102名患者进行这项研究。在患者维持一致的PER给药方案至少21天后测定稳态浓度。使用液相色谱-串联质谱法测量血浆PER浓度。来自标准治疗药物监测的剩余样品被分配用于基因分型分析。疗效的主要衡量标准是最终检查时PER治疗的癫痫发作减少率。
结果：CYP3A4×10GC表型表现出最高的平均血浆浓度为491.1±328.1ng/mL，与334.0±161.1ng/mL的CC表型相反。不良事件发生率以CYP3A4×1GTT和CYP3A4×10GC组最为突出,发生率为77.8%(9例患者中的7例)和50.0%(92例患者中的46例)，分别。此外，在CYP3A4×1GTT和CYP3A4×10CC组中，认为PER无效的患者百分比最少，记录为11.1%(9例患者中的1例)和10.0%(10例患者中的1例)，分别。PER血浆浓度与暴露或毒性之间存在显着相关性（均为p<0.05）。我们建议将血浆浓度范围为625-900ng/mL作为中国癫痫患者PER的合适参考。
结论：CYP3A4×10基因的遗传多态性影响中国小儿癫痫患者的血浆PER浓度。鉴于疗效和潜在毒性与血浆PER水平密切相关，在给癫痫患者开PER时,应考虑CYP3A4基因表型.
方法：我们招募了102名患者进行这项研究。在患者维持一致的PER给药方案至少21天后测定稳态浓度。使用液相色谱-串联质谱法测量血浆PER浓度。来自标准治疗药物监测的剩余样品被分配用于基因分型分析。疗效的主要衡量标准是最终检查时PER治疗的癫痫发作减少率。
结果：CYP3A4×10GC表型表现出最高的平均血浆浓度为491.1±328.1ng/mL，与334.0±161.1ng/mL的CC表型相反。不良事件发生率以CYP3A4×1GTT和CYP3A4×10GC组最为突出,发生率为77.8%(9例患者中的7例)和50.0%(92例患者中的46例)，分别。此外，在CYP3A4×1GTT和CYP3A4×10CC组中，认为PER无效的患者百分比最少，记录为11.1%(9例患者中的1例)和10.0%(10例患者中的1例)，分别。PER血浆浓度与暴露或毒性之间存在显着相关性（均为p<0.05）。我们建议将血浆浓度范围为625-900ng/mL作为中国癫痫患者PER的合适参考。
结论：CYP3A4×10基因的遗传多态性影响中国小儿癫痫患者的血浆PER浓度。鉴于疗效和潜在毒性与血浆PER水平密切相关，在给癫痫患者开PER时,应考虑CYP3A4基因表型.
