Worm Margitta, Nguyen DucTung, Rackley Russ, Muraro Antonella, Du Toit George, Lawrence Tracey, Li Hong, Brumbaugh Kurt, Wickman Magnus
Division of Allergy and Immunology, Department of Dermatology and Allergy, Charité Universitätsmedizin, Berlin, Germany.
Meda Pharma GmbH & Co KG, Bad Homburg vor der Hӧhe, Germany.
Clin Transl Allergy. 2020 Jun 10;10:21. doi: 10.1186/s13601-020-00326-x. eCollection 2020.
Intramuscular (IM) injection of epinephrine (adrenaline) at the mid-anterolateral (AL) thigh is the international standard therapy for acute anaphylaxis. Concerns exist regarding implications of epinephrine auto-injector needles not penetrating the muscle in patients with greater skin-to-muscle-distances (STMD).
This open-label, randomized, crossover study investigated pharmacokinetics and pharmacodynamics following injection of epinephrine in healthy volunteers. Individuals were stratified by maximally compressed STMD (low, < 15 mm; moderate, 15-20 mm; high, > 20 mm). Participants received epinephrine injections via EpiPen Auto-Injector (EpiPen; 0.3 mg/0.3 mL) or IM syringe (0.3 mg/0.3 mL) at mid-AL thigh or received saline by IM syringe in a randomized order. Eligible participants received a fourth treatment (EpiPen [0.3 mg/0.3 mL] at distal-AL thigh). Model-independent pharmacokinetic parameters and pharmacodynamics were assessed.
There were numerical trends toward higher peak epinephrine concentrations (0.52 vs 0.35 ng/mL; geometric mean ratio, 1.40; 90% CI 117.6-164.6%) and more rapid exposure (time to peak concentration, 20 vs 50 min) for EpiPen vs IM syringe at mid-AL thigh across STMD groups. Absorption was faster over the first 30 min for EpiPen vs IM syringe (partial area under curve [AUC] over first 30 min: geometric mean ratio, 2.13; 90% CI 159.0-285.0%). Overall exposure based on AUC to the last measurable concentration was similar for EpiPen vs IM syringe (geometric mean ratio, 1.13; 90% CI 98.8-129.8%). Epinephrine pharmacokinetics after EpiPen injection were similar across STMD groups. Treatments were well tolerated.
Epinephrine delivery via EpiPen resulted in greater early systemic exposure to epinephrine vs IM syringe as assessed by epinephrine plasma levels. Delivery via EpiPen was consistent across participants with a wide range of STMD, even when the needle may not have penetrated the muscle.This trial was registered with the German Clinical Trials Register (DRKS-ID: DRKS00011263; secondary ID, EudraCT 2016-000104-29) on 23 March 2017.
在大腿前外侧中部进行肾上腺素肌内注射是急性过敏反应的国际标准治疗方法。对于皮肤至肌肉距离（STMD）较大的患者，存在肾上腺素自动注射器针头未刺入肌肉的问题。
本开放标签、随机、交叉研究调查了健康志愿者注射肾上腺素后的药代动力学和药效学。个体按最大压缩STMD分层（低，<15毫米；中，15 - 20毫米；高，>20毫米）。参与者通过肾上腺素自动注射器（EpiPen；0.3毫克/0.3毫升）或肌内注射器（0.3毫克/0.3毫升）在大腿前外侧中部接受肾上腺素注射，或以随机顺序通过肌内注射器接受生理盐水注射。符合条件的参与者接受第四种治疗（在大腿前外侧远端注射EpiPen[0.3毫克/0.3毫升]）。评估了非模型依赖的药代动力学参数和药效学。
在各STMD组中，与肌内注射器相比，通过EpiPen在大腿前外侧中部注射时，肾上腺素峰值浓度有升高的数值趋势（0.52对0.35纳克/毫升；几何平均比，1.40；90%CI 117.6 - 164.6%），且暴露更快（达峰时间，20对50分钟）。在最初30分钟内，EpiPen的吸收比肌内注射器更快（最初30分钟的曲线下部分面积[AUC]：几何平均比，2.13；90%CI 159.0 - 285.0%）。基于AUC至最后可测量浓度的总体暴露，EpiPen与肌内注射器相似（几何平均比，1.13；90%CI 98.8 - 129.8%）。各STMD组中EpiPen注射后的肾上腺素药代动力学相似。治疗耐受性良好。
通过EpiPen给药导致的肾上腺素早期全身暴露比肌内注射器给药时更高，这通过肾上腺素血浆水平评估得出。即使针头可能未刺入肌肉，在具有广泛STMD的参与者中，通过EpiPen给药是一致的。本试验于2017年3月23日在德国临床试验注册中心注册（DRKS-ID：DRKS00011263；二级ID，EudraCT 2016 - 000104 - 29）。
