Zhang Jack Yongfeng, Luo Mary Ziping, Marrs Tony, Kerwin Edward M, Bukstein Don A
Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, California, USA.
Clinical Research Institute and Allergy & Asthma Center, Medford, Oregon, USA.
J Aerosol Med Pulm Drug Deliv. 2025 Apr;38(2):71-82. doi: 10.1089/jamp.2024.0025. Epub 2024 Aug 29.
Primatene MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The C in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. NCT04207840.
普米克令舒（Primatene MIST）是一种肾上腺素定量吸入器（MDI），尽管已获得美国食品药品监督管理局的批准，但长期以来一直受到一些医学专业人士对其用于哮喘治疗的质疑。他们担忧的主要原因之一源于肾上腺素给药后可能出现的心血管并发症。然而，大多数已记录的心血管并发症似乎发生在肾上腺素注射给药途径之后。本研究的目的是评估通过不同给药途径递送的肾上腺素的全身暴露情况，并了解其与心血管效应的关系。由于沙丁胺醇吸入器通常被推荐用于治疗哮喘，因此也将沙丁胺醇作为对照药物进行了研究。在28名健康成年受试者中进行了一项随机、评估者盲法、三臂交叉研究，以比较MDI递送的肾上腺素与肾上腺素肌肉注射（IM）以及沙丁胺醇MDI的全身暴露情况。在治疗组之间测量并比较了连续采样的血浆肾上腺素和沙丁胺醇水平。通过不良事件、连续生命体征、心电图（ECG）以及每次交叉给药访视时获得的临床实验室检查来评估安全性。剂量标准化后，吸入型肾上腺素MDI（39 pg/mL×小时）的全身外源性药物暴露比肾上腺素IM（435 pg/mL×小时）低约9倍，比沙丁胺醇MDI（3453 pg/mL×小时）低122倍。肾上腺素MDI的Cmax（345 pg/mL）约为肾上腺素IM（816 pg/mL）和沙丁胺醇MDI（681 pg/mL）的一半。肾上腺素MDI的血浆药物浓度迅速降至基线（约0.6小时），而肾上腺素IM需要约8小时，沙丁胺醇MDI则需要超过24小时。肾上腺素MDI和沙丁胺醇MDI导致生命体征和心电图的变化极小，临床意义不大，而肾上腺素IM导致收缩压、心率和校正QT间期出现轻度短暂升高。肾上腺素MDI（普米克令舒）的全身药物暴露（SDE）比肾上腺素IM低约9倍，比沙丁胺醇MDI低约122倍。吸入型肾上腺素较低的SDE也与令人放心的安全性结果相关，与肾上腺素IM注射后出现的短暂效应相比，未发现明显的心血管不良反应。NCT04207840。
