Patsalos Philip N, Gougoulaki Marilia, Sander Josemir W
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical & Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London and Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, United Kingdom.
Ther Drug Monit. 2016 Jun;38(3):358-64. doi: 10.1097/FTD.0000000000000274.
Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations.
We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy.
In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance.
PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.
吡仑帕奈（PMP）是一种非竞争性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体拮抗剂，是一种新型抗癫痫药物（AED），已获许可用于局灶性和全身性癫痫的辅助治疗。关于PMP的药代动力学以及与同时使用的抗癫痫药物的药物相互作用特征的信息有限。我们研究了PMP剂量、年龄、性别以及联合使用的抗癫痫药物对血清PMP浓度的影响。
我们使用了一家三级癫痫转诊中心治疗药物监测部门的数据库，以确定接受PMP治疗的患者，并从他们的病历中提取临床信息。使用液相色谱/质谱法测定血清PMP浓度。
总共鉴定出107例年龄在18至70岁之间、体重在40至125千克之间的患者（66名女性）的160份血清。他们的PMP中位剂量为6毫克/天（范围为2至12毫克/天），并联合使用了多种抗癫痫药物，包括酶诱导剂[卡马西平（CBZ）和奥卡西平（OXC）]和酶抑制剂（丙戊酸）抗癫痫药物。观察到PMP剂量与血清浓度之间存在线性关系（r = 0.714，P < 0.0005）。发现性别和年龄不影响PMP血清浓度。酶诱导性抗癫痫药物剂量依赖性地降低PMP浓度，CBZ和OXC分别使平均值降低69%和37%。相比之下，尽管托吡酯和苯妥英也分别使PMP平均浓度降低了18%和13%，但这些变化未达到统计学显著性。
PMP呈现线性剂量-浓度关系，血清PMP浓度与年龄和性别无关。CBZ和OXC可显著降低PMP浓度，可能是通过诱导CYP3A4介导的代谢。
