Segal Eric B, Wheless James W, Zafar Muhammad, Shih Evelyn K, Ngo Leock Y, Carrazana Enrique, Rabinowicz Adrian L
Hackensack University Medical Center, Northeast Regional Epilepsy Group, and Hackensack Meridian School of Medicine, Hackensack, New Jersey, USA.
Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Epilepsia. 2025 Jul 12. doi: 10.1111/epi.18473.
Benzodiazepine immediate-use seizure medications (ISMs; also called rescue therapies) are used to treat seizure clusters/acute repetitive seizures in patients with epilepsy. In the United States, diazepam nasal spray is an approved ISM for patients ≥2 years of age. The primary objective was to assess diazepam nasal spray pharmacokinetics (PK) in patients 2-5 years of age; safety and tolerability were secondary objectives.
This Phase 1/2a, open-label, single-dose, PK study with a 180-day open-label safety period enrolled patients with epilepsy 2-5 years of age. Diazepam nasal spray (0.5-mg/kg per diazepam rectal gel dosing) was administered by a medical professional, followed by PK sampling. During the safety period, caregivers administered diazepam nasal spray as needed for frequent or acute repetitive seizures. Seizures and dosing were recorded in a diary. Study visits included safety evaluations. Use of second doses was a proxy for effectiveness.
Thirty-six patients were enrolled, with 35 in the PK population. PK parameters and modeling were comparable to older children and adults, confirming that diazepam nasal spray was readily absorbed and supporting the adequacy of the 0.5-mg/kg dose for this age group. In the open-label period, second doses within 24 h of the initial dose were administered for 16.3% of seizure events (37/227), indicating that a second dose was not used for most seizure events (83.7%). Treatment-related treatment-emergent adverse events occurred in seven patients (19.4%); all were mild except one (moderate). There was one report each of respiratory depression and respiratory distress; neither was treatment related.
This study characterizes the PK of diazepam in patients 2-5 years of age and reports a safety profile consistent with older patients. Results demonstrate that the diazepam nasal spray drug-device combination is appropriate for drug delivery and absorption in these patients.
苯二氮䓬类速效抗癫痫药物（ISMs，也称为急救疗法）用于治疗癫痫患者的癫痫持续状态/急性反复性癫痫发作。在美国，地西泮鼻喷雾剂是一种已获批用于≥2岁患者的ISMs。主要目的是评估2至5岁患者使用地西泮鼻喷雾剂的药代动力学（PK）；安全性和耐受性为次要目的。
这项1/2a期、开放标签、单剂量PK研究设有180天的开放标签安全观察期，纳入了2至5岁的癫痫患者。由医疗专业人员给予地西泮鼻喷雾剂（按地西泮直肠凝胶剂量为0.5mg/kg），随后进行PK采样。在安全观察期内，照料者根据需要为频繁或急性反复性癫痫发作给予地西泮鼻喷雾剂。癫痫发作和给药情况记录在日记中。研究访视包括安全性评估。使用第二剂作为有效性的替代指标。
共纳入36例患者，其中35例进入PK分析人群。PK参数和模型与年龄较大的儿童及成人相当，证实地西泮鼻喷雾剂易于吸收，并支持该年龄组0.5mg/kg剂量的充足性。在开放标签期，初始剂量后24小时内有16.3%的癫痫发作事件（37/227）给予了第二剂，这表明大多数癫痫发作事件（83.7%）未使用第二剂。7例患者（19.4%）发生了与治疗相关的治疗中出现的不良事件；除1例（中度）外，均为轻度。各有1例呼吸抑制和呼吸窘迫报告；均与治疗无关。
本研究描述了2至5岁患者使用地西泮的PK情况，并报告了与年龄较大患者一致的安全性概况。结果表明，地西泮鼻喷雾剂药物装置组合适用于这些患者的药物递送和吸收。
