We agree with Mudigoudar and Wheless. Cenobamate is generally well tolerated, but some patients can develop dizziness, drowsiness, and other CNS-related symptoms when cenobamate is titrated rapidly to high doses (usually >200 mg per day) in combination with treatment with high doses of sodium channel modulators. Cenobamate is approved to be titrated slowly over 11 weeks to 200 mg per day, which usually mitigates pharmacodynamic interactions. The titration schedule used in our clinical trial referenced by Mudigoudar and Wheless was much quicker (weekly titration). Furthermore, placebo-controlled adjunctive treatment trials for regulatory approval by the US Food and Drug Administration differ from clinical practice in requiring patients to continue concomitant antiepileptic drugs at fixed doses. In open treatment phases of cenobamate trials, we often reduced doses of previously ineffective sodium channel antiepileptic drugs, while optimising cenobamate doses. This conversion was effective in optimising cenobamate therapy for many patients. We previously showed that so-called cross-titrating between sodium channel modulators is an effective method for optimising tolerability and dosing of a new antiepileptic drug. Pharmacodynamic interactions between sodium ion channel modulators and associated symptoms such as dizziness and imbalance are probably due to gating effects on rapidly firing neurons in the brainstem and cerebellum (eg, Purkinje neurons and vestibular and oculomotor nuclei). Cenobamate modulates slowly inactivating sodium ion channels but also modulates a persistent sodium channel current and currents mediated by the GABA_A receptor.^,  These mechanisms could potentially contribute to its strong efficacy for adjunctive treatment of medication-resistant focal-onset epilepsy; this efficacy usually permits dose reductions and conversion from previous ineffective therapies.

中文翻译：

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局灶性癫痫发作无法控制的患者使用塞巴氨基丁酸辅助治疗的安全性-作者的回复。

我们同意Mudigoudar和Wheless的观点。百草枯通常具有良好的耐受性，但是当将百草枯快速滴定至高剂量（通常每天> 200 mg）并与高剂量钠通道调节剂联合使用时，某些患者会出现头晕，嗜睡和其他与中枢神经系统相关的症状。批准将Cenobamate在11周内缓慢滴定至每天200 mg，这通常可以减轻药效相互作用。由Mudigoudar和Wheless引用的我们的临床试验中使用的滴定时间表要快得多（每周滴定）。此外，获得美国食品和药物管理局（FDA）批准的安慰剂对照辅助治疗试验与临床实践的不同之处在于，它要求患者继续以固定剂量同时服用抗癫痫药。在斑柏酸酯试验的开放治疗阶段，我们经常减少以前无效的钠通道抗癫痫药的剂量，同时优化Cenobamate的剂量。这种转换有效地优化了许多患者的苯巴比妥疗法。我们先前表明，钠通道调节剂之间的所谓交叉滴定是一种优化耐受性和新抗癫痫药剂量的有效方法。钠离子通道调节剂与相关症状（如头昏眼花和不平衡）之间的药效相互作用可能是由于门控作用对快速激发的脑干和小脑神经元（例如浦肯野神经元以及前庭和动眼神经核）造成的。烯诺酸盐调节缓慢失活的钠离子通道，但也调节持久的钠通道电流和由GABA介导的电流_一个受体。^， 这些机制可能促进其强大的功效为耐药物焦性癫痫的辅助治疗; 这种功效通常允许减少剂量并从先前无效的治疗方法中转换出来。