背景:延迟治疗麻醉诱导的恶性高热会增加并发症和死亡的风险。NPJ5008是一种新型的治疗方法,丹曲林钠,与参考制剂DANTRIUMIV相比,已开发用于缩短制备和给药时间。已在临床前比较了这两种制剂。
目的:评估丹曲林(游离酸)整体暴露于NPJ5008与丹曲林IV的生物等效性,并确定它们在药代动力学和安全性/耐受性方面的相似性。评估新制剂的制备/给药时间节省。
方法:这项人类开放标签试验的第1部分是一项1:1随机交叉研究;第2部分是单臂研究。试验药学数据和实验室模拟评估了制备/施用步骤的时间安排。
方法:英国的单一临床中心,2021年4月至7月。
方法:21名健康男性和女性个体。
方法:第1部分:单次静脉注射60mg剂量的NPJ5008或DANTRIUMIV,顺序。第2部分:单次静脉内120mg剂量的NPJ5008。模拟:使用儿科和成人插管的每个制剂五个小瓶。
方法:总体药物暴露至最后可测量浓度(AUC0至最后)和外推到无穷大(AUC0至∞)是主要终点。其他药代动力学,临床和肌肉功能参数,和不良事件,被监控。
结果:调整后的NPJ5008与DANTRIUMIV的几何平均比率分别为90.24%和90.44%,AUC0至∞,分别,90%置信区间(CI)在80%到125%接受区间内,建立生物等效性。没有出现新的安全性问题:任何不良事件在治疗中的程度相似,并且与丹曲林的药理特性有关。药学和模拟数据显示,NPJ5008的制备和给药的每个步骤都比DANTRIUMIV快26%至69%。
结论:NPJ5008显示出与DANTRIUMIV相当的药代动力学和安全性,同时减少丹曲林剂量制备/给药时间,可能减少恶性高热患者的并发症/医疗资源。
背景:EudraCT编号:2020-005719-35,MHRA批准。
BACKGROUND: Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.
OBJECTIVE: Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.
METHODS: Part 1 of this open-label
trial in humans was a 1 : 1 randomised crossover
study; part 2 was a single-arm
study.
Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.
METHODS: Single clinical centre in the UK, April to July 2021.
METHODS: Twenty-one healthy male and female individuals.
METHODS: Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.
METHODS: Overall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.
RESULTS: Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.
CONCLUSIONS: NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.
BACKGROUND: EudraCT Number: 2020-005719-35, MHRA approval.