Henney Herbert R, Sperling Michael R, Rabinowicz Adrian L, Bream Gary, Carrazana Enrique J
Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA.
Department of Neurology, Thomas Jefferson University, 901 Walnut Street, Suite 400, Philadelphia, PA 19107, USA.
Epilepsy Res. 2014 Sep;108(7):1204-11. doi: 10.1016/j.eplepsyres.2014.04.007. Epub 2014 May 13.
Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability to that of diazepam-RG. The intranasal formulation may provide caregivers and patients with a more socially acceptable and convenient alternative rescue therapy in the acute treatment of seizure clusters.
地西泮直肠凝胶（RG）目前是美国唯一获批用于门诊治疗癫痫持续状态的急救疗法。对于癫痫持续状态，存在对有效且给药更方便、社会可接受的给药方式的替代急救疗法的未满足医疗需求。一种鼻内地西泮制剂已被研发出来，本研究评估了地西泮鼻喷雾剂（NS）相对于等效剂量地西泮-RG在健康成年人中的耐受性和生物利用度。24名健康成年人参与了一项1期、开放标签、3期交叉研究。通过连续采样测量血浆地西泮和代谢物浓度。通过最大血浆浓度（Cmax）和全身暴露参数（AUC0-∞和AUC0-24）评估5毫克和20毫克鼻内剂量的剂量比例以及20毫克地西泮-NS相对于20毫克地西泮-RG的生物利用度。20毫克地西泮-NS和20毫克地西泮-RG的平均Cmax值分别为378±106和328±152纳克/毫升，分别在1.0小时和1.5小时达到。接受鼻内和直肠凝胶制剂的受试者分别出现了鼻腔和直肠渗漏。鼻内给药后地西泮的吸收是一致的，但3名接受地西泮-RG的受试者在最早5分钟评估时血浆药物水平较低，原因是保留不佳，被排除在分析之外。排除他们后，地西泮Cmax和AUC0-24的治疗比率（20毫克地西泮-NS：20毫克地西泮-RG）及90%置信区间分别为0.98（0.85-1.14）和0.89（0.80-0.98），表明两种制剂的生物利用度相当。在鼻内制剂的最低和最高剂量强度之间观察到了剂量比例关系。鼻内和直肠治疗的耐受性都很好，不良事件为轻度至中度。结果表明，单剂量20毫克地西泮-NS耐受性良好，生物利用度与地西泮-RG相当。鼻内制剂可能为护理人员和患者在癫痫持续状态的急性治疗中提供一种社会更可接受且更方便的替代急救疗法。
