A Phase 1, Five-Period, Five-Treatment, Randomized Crossover Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Epinephrine After Administration of Intranasal (IN) ARS-1 and Intramuscular (IM) Epinephrine to Healthy Volunteers

An epinephrine nasal spray (1mg ARS-1) is being developed for the emergency treatment of systemic allergic reactions including anaphylaxis as a needle-free alternative to autoinjectors. This study compares the pharmacokinetics and hemodynamic responses (PK/PD relationship) of epinephrine administered by the IN route with IM injection in the mid-anterolateral thigh using a needle and syringe. Seventy healthy adults were randomized in a cross-over design to receive1mg IN once or twice, 0.3mg IM once or twice and 0.5mg IM. Extensive pharmacokinetic sampling and hemodynamic measurements (BP each 4min and continuous ECG) were conducted. Safety assessments include adverse events (AEs), nasal irritation and pain. Epinephrine AUC0-tfrom IN administration compared to 0.3mg IM was bioequivalent after one (ratio 102%; 90%CI 91-114%) and two (ratio 95%; 90%CI 85-106%) doses given 5-minutes apart. The rate of absorption of ARS-1 was more rapid than IM injection based on tmax (20min vs. 45min), time to 100pg/mL and partial-AUCs. The more rapid absorption of epinephrine from IN administration resulted in a faster and greater increase in HR and SBP, as well as a higher Cmaxthan 0.3mg but ∼16% lower than 0.5mg IM. ARS-1 gave more consistent exposure and hemodynamic response in the first 20mins. ARS-1 was well tolerated with mild AEs and no irritation or pain. Epinephrine IN (1mg ARS-1) was bioequivalent (AUC) to 0.3mg IM injection, but was absorbed more rapidly resulting in a significantly improved hemodynamic response (increased SBP and HR). ARS-1 (IN epinephrine) has promise as a needle-free alternative to IM epinephrine.