PII-140 - PHARMCOKINETIC AND PHARMACODYNAMIC RELATIONSHIPS OF INTRANASALLY ADMINISTERED AND INTRAMUSCULARLY INJECTED EPINEPHRINE

A. van Haarst¹, S. Paglialunga², M. Di Spirito³, A. Lambert³, A. Hunt³, A. Vinks⁴, T. Mizuno⁵, R. Tanaka⁶, K. Rance⁷, D. Dworaczyk⁷; ¹Celerion, Belfast, United Kingdom, ²Celerion, Tempe, AZ, US, ³Celerion, ⁴Cincinnati Children's Hospital, Division of Clinical Pharmacology, ⁵Cincinnati Children's Hospital Medical Center, ⁶Cincinnati Children's Hospital Medical Center, ⁷Bryn Pharma, LLC..

Background: While intramuscular (IM) administration of epinephrine (EPI) is a first-line treatment of anaphylaxis, intranasal (IN) EPI may offer a faster route of administration, avoiding reluctance to IM injection and application error. EPI acts on alpha and beta-adrenergic receptors, thus counteracting vasodilation, vascular permeability, and hypotension during anaphylaxis. Because EPI has an intrinsic potential to affect heart rate (HR) and systolic (SBP) and diastolic blood pressure (SBP) through activation of beta-adrenergic receptors, the effects of IN administered EPI were compared to IM EPI.

Methods: During the first study period of 3 distinct clinical trials, healthy subjects received a single IN dose of either 6.6 mg (N=11) or 13.2 mg EPI (N=79) (NSD1C; 13.2 mg given as 2 × 6.6 mg consecutive sprays in the same or opposite nostrils), or a single IM EPI injection by EpiPen® autoinjector (0.3 mg)(N=50) or by manual syringe (0.5 mg)(N=42). Maximum EPI concentrations (Cmax) and corresponding maximum changes from baseline (Emax) for HR, SBP and DBP from these studies were combined for each treatment, and data were compared using Microsoft Excel and R software (version 4.1).

Results: Mean (CV%) Cmax values were 178 (98.2), 634 (142.5), 368 (54.9) and 847 (329.5) pg/mL for 6.6 mg IN, 13.2 mg IN, 0.3 mg IM and 0.5 mg IM EPI, respectively. Mean (CV%) Emax values were: for HR, 19.8 (4.95), 26.8 (18.8), 22.9 (14.7) and 26.7 (15.6) bpm for 6.6 mg IN, 13.2 mg IN, 0.3 mg IM and 0.5 mg IM EPI; for SBP 14.0 (11.3), 16.3 (12.6), 17.8 (10.7) and 15.8 (9.26) mmHg for 6.6 mg IN, 13.2 mg IN, 0.3 mg IM and 0.5 mg IM EPI; and for DBP 11.5 (8.48), 10.7 (7.92), 11.5 (6.96) and 10.6 (6.92) mmHg for 6.6 mg IN, 13.2 mg IN, 0.3 mg IM and 0.5 mg IM EPI, respectively. Overall, there were no statistical or clinically meaningful differences in HR, SBP or DBP across all treatment groups (IN- and IM-administered EPI).

Conclusion: IN administered EPI (6.6 and 13.2 mg) has comparable effects on HR, SBP, and DBP as IM-injected EPI (0.3 and 0.5 mg), with similar variability and maximum effects. The apparent plateau of EPI effects on cardiovascular parameters at the attained plasma concentrations align with findings published by others.