Brodie Martin J, Fakhoury Toufic, McDonough Belinda, Colson Anny-Odile, Stockis Armel, Elmoufti Sami, Whitesides John
Epilepsy Unit, West Glasgow ACH-Yorkhill, Glasgow, UK.
St. Joseph Health System, Lexington, KY, USA.
Epilepsy Res. 2018 Sep;145:55-62. doi: 10.1016/j.eplepsyres.2018.06.002. Epub 2018 Jun 4.
To assess the association, if any, between brivaracetam (BRV)-induced elevated carbamazepine-10,11-epoxide (CBZ-E) and toxicity and efficacy in patients with epilepsy. Data were pooled from three double-blind, placebo-controlled, Phase III studies of adjunctive BRV in adults with uncontrolled focal seizures (N01252/NCT00490035, N01253/NCT00464269, N01358/NCT01261325). Treatment-emergent adverse events (TEAEs) of interest (ataxia, diplopia, dizziness, nystagmus, somnolence, accidental overdose or poisoning, and toxicity), discontinuations due to TEAEs, and serious TEAEs (SAEs) were assessed in subgroups who did/did not receive carbamazepine (CBZ) at study entry (CBZ+ and CBZ-). Logistic regression analysis evaluated CBZ-E/CBZ plasma concentrations and TEAEs. SAEs suggestive of CBZ-E toxicity were summarized from the BRV safety database up to a cut-off of October 1, 2014. Percent reduction in focal seizure frequency over placebo was assessed in subgroups of CBZ-E/CBZ ratios. Data from 1558 patients were included in the pooled safety population. Of these, concomitant CBZ was received by 184/459 (40.1%) placebo-treated and 315/803 (39.2%) BRV-treated patients (≥50 mg/day). In BRV-treated patients, study completion rates were similar in the CBZ+ (92.7%) and CBZ- (88.7%) groups; incidence of TEAEs of interest was similar (CBZ+ 24.4%; CBZ- 24.2%), and did not appear affected by CBZ dosage; SAEs and discontinuations due to TEAEs were CBZ+ 1.6%; CBZ- 3.9% and 2.9%; 9.2%, respectively. Likelihood of TEAEs of interest decreased with increasing CBZ-E/CBZ ratio for BRV-treated patients: odds ratio 0.88 (95% confidence intervals 0.74, 1.03; p = 0.112). In the safety database, five SAEs suggestive of CBZ-E toxicity were identified. Efficacy outcomes did not appear to have a consistent pattern across CBZ-E/CBZ ratio subgroups. This post-hoc analysis does not support an association between CBZ-E levels and TEAEs potentially associated with CBZ-E toxicity, or with increases in efficacy. Overall, current evidence does not suggest that BRV dose adjustment is required with concomitant CBZ.
评估布瓦西坦（BRV）诱导的卡马西平-10,11-环氧化物（CBZ-E）升高与癫痫患者毒性和疗效之间是否存在关联（若存在关联）。数据来自三项双盲、安慰剂对照的III期研究，这些研究为成人局灶性癫痫发作未得到控制的患者添加BRV（N01252/NCT00490035、N01253/NCT00464269、N01358/NCT01261325）。在研究入组时接受/未接受卡马西平（CBZ）的亚组（CBZ+和CBZ-）中，评估了感兴趣的治疗中出现的不良事件（TEAE，共济失调、复视、头晕、眼球震颤、嗜睡、意外过量或中毒以及毒性）、因TEAE导致的停药情况以及严重TEAE（SAE）。逻辑回归分析评估了CBZ-E/CBZ血浆浓度与TEAE。截至2014年10月1日，从BRV安全数据库中总结了提示CBZ-E毒性的SAE。在CBZ-E/CBZ比值亚组中评估了与安慰剂相比局灶性癫痫发作频率的降低百分比。汇总的安全人群纳入了1558例患者的数据。其中，184/459（40.1%）接受安慰剂治疗的患者和315/803（39.2%）接受BRV治疗的患者（≥50mg/天）同时接受了CBZ。在接受BRV治疗的患者中，CBZ+组（92.7%）和CBZ-组（88.7%）的研究完成率相似；感兴趣的TEAE发生率相似（CBZ+为24.4%；CBZ-为24.2%），且似乎不受CBZ剂量影响；因TEAE导致的SAE和停药率分别为CBZ+组1.6%；CBZ-组3.9%和2.9%；9.2%。接受BRV治疗的患者中，随着CBZ-E/CBZ比值增加，感兴趣的TEAE发生可能性降低：比值比为0.88（95%置信区间0.74，1.03；p = 0.112）。在安全数据库中，确定了5例提示CBZ-E毒性的SAE。在CBZ-E/CBZ比值亚组中，疗效结果似乎没有一致的模式。这项事后分析不支持CBZ-E水平与可能与CBZ-E毒性相关的TEAE或疗效增加之间存在关联。总体而言，目前的证据不表明同时使用CBZ时需要调整BRV剂量。
