Cohen Hagar, Mahajna Ghadeer, Ben-Shushan Tomer, Matok Ilan, Eyal Sara
Department of Clinical Pharmacy, Faculty of Medicine, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel.
Medical Library Authority, Hebrew University of Jerusalem, Jerusalem, Israel.
Epilepsia. 2024 Feb;65(2):445-455. doi: 10.1111/epi.17822. Epub 2023 Dec 11.
Antiseizure medications (ASMs) are commonly categorized as enzyme-inducers and non-enzyme-inducers based on their propensity to enhance the metabolism of concomitantly administered drugs. This systematic review and network meta-analysis aimed to rank ASMs as cytochrome P450 3A (CYP3A)-inducers based on a comparative assessment of ASM-induced reduction in the concentrations of sensitive substrate drugs.
The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42022335846), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) standards were followed. We searched MEDLINE, Embase, and Cochrane until March 14, 2023 without an initial date restriction. Data were additionally obtained via the US Food and Drug Administration database. Studies had to be prospective, with ASM monotherapy for ≥5 days. The primary parameter was the magnitude of change in the area under the concentration-time curve of CYP3A substrates following treatment with the ASM. The standardized mean difference (SMD) was used as the point estimate for the indirect comparisons between ASMs using the pairwise method. Bias risk was assessed using the PKclin tool.
We identified 14 open-label, fixed-sequence studies with 370 participants. The effect size of 600 mg/day carbamazepine did not differ from those of 300 mg/day phenytoin (SMD = -.06, 95% confidence interval [CI] = -.18 to .07) and 200 mg/day cenobamate (SMD = -.11, 95% CI = -.26 to .04). Carbamazepine at 600 mg/day was the strongest CYP3A-inducer (P-score = .88), followed by carbamazepine 400 mg/day (.83), phenytoin 300 mg/day (.79), and cenobamate 200 mg/day (.73). Eslicarbazepine (800 mg/day) ranked higher than cenobamate 100 mg/day and oxcarbazepine 900 mg/day (.60, .39, and .37, respectively).
Despite the limited number of studies, our network meta-analysis emphasizes that the magnitude of ASM effects on CYP3A substrate metabolism is a dose-dependent continuum. When possible, ASM classification as inducers should apply cutoff values tailored to the outcome. Prescribers should monitor plasma concentrations or clinical effects of CYP3A substrates and consider selecting concomitant medications accordingly.
抗癫痫药物（ASMs）通常根据其增强同时服用药物代谢的倾向分为酶诱导剂和非酶诱导剂。本系统评价和网络荟萃分析旨在根据对ASM诱导的敏感底物药物浓度降低的比较评估，将ASMs列为细胞色素P450 3A（CYP3A）诱导剂。
该方案已在PROSPERO（国际系统评价前瞻性注册库；CRD42022335846）注册，并遵循PRISMA（系统评价和荟萃分析的首选报告项目）标准。我们检索了MEDLINE、Embase和Cochrane数据库，直至2023年3月14日，无初始日期限制。还通过美国食品药品监督管理局数据库获取了数据。研究必须是前瞻性的，采用ASM单药治疗≥5天。主要参数是ASM治疗后CYP3A底物浓度-时间曲线下面积的变化幅度。使用标准化均数差（SMD）作为采用成对法进行ASM间接比较的点估计值。使用PKclin工具评估偏倚风险。
我们确定了14项开放标签、固定序列研究，共370名参与者。600mg/天卡马西平的效应大小与300mg/天苯妥英钠（SMD = -0.06，95%置信区间[CI] = -0.18至0.07）和200mg/天司替戊醇（SMD = -0.11，95%CI = -0.26至0.04）的效应大小无差异。600mg/天的卡马西平是最强的CYP3A诱导剂（P评分 = 0.88），其次是400mg/天的卡马西平（0.83）、300mg/天的苯妥英钠（0.79）和200mg/天的司替戊醇（0.73）。依斯立康唑（800mg/天）的排名高于100mg/天的司替戊醇和900mg/天的奥卡西平（分别为0.60、0.39和0.37）。
尽管研究数量有限，但我们的网络荟萃分析强调，ASM对CYP3A底物代谢的影响程度是一个剂量依赖性的连续体。在可能的情况下，将ASM分类为诱导剂应应用根据结果量身定制的临界值。处方者应监测CYP3A底物的血浆浓度或临床效果，并相应地考虑选择同时使用的药物。
