Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
目的：抗癫痫药物（ASM）通常根据其增强伴随给药药物代谢的倾向分为酶诱导剂和非酶诱导剂。这项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，将单个ASM列为细胞色素P450（CYP）3A诱导剂。
方法：该方案已在PROSPERO（CRD4202235846）注册，并遵循PRISMA标准。我们搜索了MEDLINE,EMBASE,和Cochrane，直到2023年3月14日，没有初始日期限制。另外通过FDA数据库获得数据。研究必须是前瞻性的，ASM单药治疗≥5天。主要参数是用ASM处理后CYP3A底物的浓度-时间曲线下面积(AUC)的变化幅度。使用标准化平均差（SMD）作为使用成对方法在ASM之间进行间接比较的点估计。使用PKclin工具评估偏差风险。
结果：我们确定了14个开放标签，370名参与者的固定序列研究。600mg/天的卡马西平的作用大小与300mg/天的苯妥英（SMD-0.06;95CI-0.18-0.07）和200mg/天的锡溴酸盐（SMD-0.11;95CI-0.26-0.04）的作用大小没有差异。卡马西平600毫克/天是最强的CYP3A诱导剂（P评分0.88），其次是卡马西平400毫克/天（0.83），苯妥英300毫克/天（0.79），和cenobamate200毫克/天（0.73）。Esilicarbazepine（800mg/天）的排名高于锡丁酸酯100mg/天和奥卡西平900mg/天（分别为0.60、0.39和0.37）。
结论：尽管研究数量有限，我们的NMA强调ASM对CYP3A底物代谢的影响程度是剂量依赖性的连续性。如果可能,作为诱导物的ASM分类应应用针对结果定制的截止值。处方者应监测血浆浓度或CYP3A底物的临床效果，并考虑相应地选择合并用药。
方法：该方案已在PROSPERO（CRD4202235846）注册，并遵循PRISMA标准。我们搜索了MEDLINE,EMBASE,和Cochrane，直到2023年3月14日，没有初始日期限制。另外通过FDA数据库获得数据。研究必须是前瞻性的，ASM单药治疗≥5天。主要参数是用ASM处理后CYP3A底物的浓度-时间曲线下面积(AUC)的变化幅度。使用标准化平均差（SMD）作为使用成对方法在ASM之间进行间接比较的点估计。使用PKclin工具评估偏差风险。
结果：我们确定了14个开放标签，370名参与者的固定序列研究。600mg/天的卡马西平的作用大小与300mg/天的苯妥英（SMD-0.06;95CI-0.18-0.07）和200mg/天的锡溴酸盐（SMD-0.11;95CI-0.26-0.04）的作用大小没有差异。卡马西平600毫克/天是最强的CYP3A诱导剂（P评分0.88），其次是卡马西平400毫克/天（0.83），苯妥英300毫克/天（0.79），和cenobamate200毫克/天（0.73）。Esilicarbazepine（800mg/天）的排名高于锡丁酸酯100mg/天和奥卡西平900mg/天（分别为0.60、0.39和0.37）。
结论：尽管研究数量有限，我们的NMA强调ASM对CYP3A底物代谢的影响程度是剂量依赖性的连续性。如果可能,作为诱导物的ASM分类应应用针对结果定制的截止值。处方者应监测血浆浓度或CYP3A底物的临床效果，并考虑相应地选择合并用药。
