Lipton Richard B, Kollins John A, Albrecht Detlef
Department of Neurology, Albert Einstein College of Medicine, and Montefiore Medical Center, Bronx, New York, USA.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, and Montefiore Medical Center, Bronx, New York, USA.
Headache. 2025 Mar;65(3):527-535. doi: 10.1111/head.14877. Epub 2024 Nov 27.
To assess the relationships between dihydroergotamine (DHE) pharmacokinetic (PK) parameters, clinical efficacy, and nausea incidence to determine a DHE PK profile that optimizes efficacy while minimizing adverse events (AEs), particularly nausea.
Dihydroergotamine is a widely used option for the acute treatment of migraine. Although multiple DHE dosage forms, with varying PK and AE profiles, have been evaluated in randomized controlled trials (RCTs), the relationships between PK profile, efficacy, and the common DHE-related AE, nausea, have not been comprehensively evaluated.
A literature search identified RCTs evaluating the efficacy (2-h pain relief [2hPR]) of different DHE dosage forms. The PK profiles for these DHE dosage forms were determined from published literature. Univariate regression analyses were performed to determine the PK parameters that best predicted 2hPR across DHE dosage forms. The relationship between maximum plasma concentration (C) and nausea incidence for various dosage forms was determined from published Phase 1 trials.
The literature search identified nine RCTs with DHE dosage forms that reported 2hPR: DHE liquid nasal spray (four studies), DHE administered subcutaneously (three), and DHE administered via oral pulmonary inhalation (two). The DHE PK parameters that best predicted 2hPR rates were C and area under the curve from time zero to 0.5 h post-dose (AUC) (R = 0.59 for each). Across Phase 1 trials, nausea incidence was minimal when C was <2500 pg/mL but increased in a log-linear manner when C exceeded ~2500 pg/mL.
The maximum concentration and AUC over the first 30 min following DHE administration were associated with increasing rates of 2hPR and a C below ~2500 pg/mL was associated with low incidences of nausea. We suggest that this may be an optimal profile for a DHE delivery form. Further research to test this hypothesis is warranted.
评估双氢麦角胺（DHE）的药代动力学（PK）参数、临床疗效和恶心发生率之间的关系，以确定能优化疗效同时将不良事件（AE）尤其是恶心降至最低的DHE PK特征。
双氢麦角胺是偏头痛急性治疗中广泛使用的药物。尽管在随机对照试验（RCT）中已对多种具有不同PK和AE特征的DHE剂型进行了评估，但PK特征、疗效与常见的与DHE相关的AE（恶心）之间的关系尚未得到全面评估。
通过文献检索确定评估不同DHE剂型疗效（2小时疼痛缓解[2hPR]）的RCT。这些DHE剂型的PK特征从已发表的文献中确定。进行单变量回归分析以确定能最佳预测不同DHE剂型2hPR的PK参数。从已发表的1期试验中确定各种剂型的最大血浆浓度（C）与恶心发生率之间的关系。
文献检索确定了9项报告2hPR的使用DHE剂型的RCT：DHE液体鼻喷雾剂（4项研究）、皮下注射DHE（3项）和经口腔肺部吸入DHE（2项）。能最佳预测2hPR率的DHE PK参数是C和给药后0至0.5小时的曲线下面积（AUC）（每项R = 0.59）。在1期试验中，当C <2500 pg/mL时恶心发生率最低，但当C超过约2500 pg/mL时以对数线性方式增加。
DHE给药后最初30分钟内的最大浓度和AUC与2hPR率增加相关，C低于约2500 pg/mL与低恶心发生率相关。我们认为这可能是DHE给药形式的最佳特征。有必要进行进一步研究来验证这一假设。
