EPINEPHRINE NASAL SPRAY (ARS-1) AND INTRAMUSCULAR INJECTION: PHARMACOKINETIC/PHARMACODYNAMIC DIFFERENCES AND DIFFERENTIAL AFFINITIES FOR ADRENERGIC RECEPTORS

Abstract

<h3>Introduction</h3> Although considered clinically indistinguishable, pharmacokinetics (PK) and pharmacodynamics (PD) between epinephrine intramuscular (IM) injection devices and manual IM injection are different. Differences in PD profiles of epinephrine products affecting blood pressure (BP) were investigated. <h3>Methods</h3> This integrated analysis was based on 4 randomized, cross-over, phase 1 studies (175 participants) comparing epinephrine manual IM 0.3 mg injection, epinephrine 0.3 mg injection devices, and epinephrine 1 mg nasal spray (ARS-1) once and twice dosing. IRB approval was obtained by all clinical sites. <h3>Results</h3> Highest mean C_max values (pg/mL) were observed following epinephrine auto-injector (503), with ARS-1 (258) comparable to manual IM (254), with the trend similar with twice-dosing. Mean systolic BP (SBP) E_max change from baseline (mm Hg) and heart rate (HR) E_max change from baseline (bpm) were comparable between ARS-1 (16.9 and 13.6, respectively) and epinephrine auto-injector (18.1 and 14.4, respectively) compared to IM (10.9 and 12.8, respectively), despite expecting that HR would correlate with epinephrine concentration due to lower affinity of β-adrenergic receptors. This trend was observed with twice dosing where mean C_max with ARS-1 and epinephrine auto-injector were 486 pg/mL versus 654 pg/mL, respectively, and mean SBP E_max (mm Hg) and HR Emax (bpm), respectively, were 25.9 and 22.6 with ARS-1 and 26.7 and 22.7 with epinephrine auto-injector. <h3>Conclusion</h3> ARS-1 increased BP more efficiently than epinephrine auto-injector or manual IM injection despite differences in C_max and t_max. This is likely due to bypassing β2 receptor-mediated vasodilatation in the skeletal muscle and stimulating β1 receptors to increase HR.