Mechanism of the first and second peaks in epinephrine pharmacokinetics over time

Abstract

Background: There is a documented double peak phenomenon following the intramuscular injection of epinephrine, however these peaks are typically representative of mean epinephrine concentrations and not individual subjects. Objective: An examination of epinephrine pharmacokinetics was conducted to explore the nature of the double peak phenomenon and to determine if the double peaks observed in mean concentration profiles were also observed in individual subjects. Methods: A GCP compliant study was conducted in 36 adult volunteers with a history of type I allergies. Blood samples were collected before and at multiple timepoints after subjects self- administered two FDA-approved epinephrine auto-injectors (EpiPen 0.3 mg and Symjepi 0.3 mg). Pharmacokinetic parameters (Cmax and tmax) and concentration-time curves were determined based on individual subjects. Subjects were categorized by their tmax (≤4 min, >4 min - ≤10 min, >10 min - ≤20 min, >20 min - ≤30 min, >30 min - ≤45 min, and >45 min, presented as ≤4 min, ≤10 min, ≤20 min, ≤30 min, ≤45 min, and >45 min, respectively). Results: The majority of individual subjects did not have double peaks. Double peaks in mean concentration-time profiles were observed when tmax was ≤4 min following EpiPen and Symjepi, tmax ≤30 min following EpiPen, and tmax ≤45 min following EpiPen. The individual epinephrine concentration curves for subjects with a tmax ≤4 min following EpiPen and Symjepi and tmax ≤45 min following EpiPen demonstrate that the majority of individual subjects do not have double peaks. Conclusion: These data suggest that the double peaks observed in mean epinephrine concentrations are likely driven by subsets of subjects with either early or late tmax values and may not necessarily be a pharmacokinetic characteristic of epinephrine.