Epinephrine delivery via EpiPen® Auto-Injector or manual syringe across participants with a wide range of skin-to-muscle distances

Margitta Worm; DucTung Nguyen; Russ Rackley; Antonella Muraro; George Du Toit; Tracey Lawrence; Hong Li; Kurt Brumbaugh; Magnus Wickman

doi:10.1186/s13601-020-00326-x

Epinephrine delivery via EpiPen^® Auto-Injector or manual syringe across participants with a wide range of skin-to-muscle distances

Clin Transl Allergy. 2020 Jun 10:10:21. doi: 10.1186/s13601-020-00326-x. eCollection 2020.

Authors

Margitta Worm¹, DucTung Nguyen², Russ Rackley³, Antonella Muraro⁴, George Du Toit^{5

6

7}, Tracey Lawrence³, Hong Li³, Kurt Brumbaugh³, Magnus Wickman⁸

Affiliations

¹ Division of Allergy and Immunology, Department of Dermatology and Allergy, Charité Universitätsmedizin, Berlin, Germany.
² Meda Pharma GmbH & Co KG, Bad Homburg vor der Hӧhe, Germany.
³ Mylan Inc, Canonsburg, PA USA.
⁴ Food Allergy Referral Centre, Department of Woman and Child Health, Padua University Hospital, Padua, Italy.
⁵ Children's Allergy Service, Evelina London, Guy's and St Thomas' Hospital, London, UK.
⁶ Department of Women and Children's Health, Pediatric Allergy, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.
⁷ MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
⁸ Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.Trial registrationsThis trial was registered with the German Clinical Trials Register (DRKS-ID: DRKS00011263; secondary ID, EudraCT 2016-000104-29) on 23 March 2017.

Keywords: Adrenaline; Anaphylaxis; Auto-injectors; Body mass index; Epinephrine; Intramuscular injections; Needle length; Obesity; Pharmacokinetics; Skin-to-muscle distance.