title: Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler.
abstract: Inhaled epinephrine is a potential alternative to self-administered intramuscular epinephrine in imminent anaphylactic reactions. The objective was to develop a pharmacokinetic-pharmacodynamic model describing exposure and effects on heart rate of inhaled epinephrine. Data from a 4-phase cross-over clinical trial in 9 healthy volunteers including 0.3 mg intramuscular epinephrine, two doses of inhaled epinephrine (4 mg/mL solution administered during [mean] 18 and 25 min, respectively) using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events. While the expected maximum concentration was higher for inhaled epinephrine, this was not associated with safety concerns due to only moderate additional hemodynamic effects compared to intramuscular administration. Bioavailability after inhalation (4.7%) was subject to high interindividual and interoccasional variability highlighting that training of inhalation would be essential for patients. The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Cologne, Germany. Electronic address: sebastian.frechen@uk-koeln.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Frechen
authors.affiliation: Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Cologne, Germany.
authors.forename: Ahmed Abbas
authors.initials: AA
authors.lastname: Suleiman
authors.affiliation: Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Cologne, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Mohammad Nejad Sigaroudi
authors.affiliation: INFECTOPHARM Arzneimittel und Consilium GmbH, Von-Humboldt-Str.1, 64646 Heppenheim, Germany.
authors.forename: Bertil
authors.initials: B
authors.lastname: Wachall
authors.affiliation: Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Cologne, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
mesh_terms: D000280:Administration, Inhalation; D000322:Adrenergic Agonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000336:Aerosols; D001682:Biological Availability; D018592:Cross-Over Studies; D004837:Epinephrine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004867:Equipment Design; D005260:Female; D005858:Germany; D006207:Half-Life; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007273:Injections, Intramuscular; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015233:Models, Statistical; D009330:Nebulizers and Vaporizers; D010865:Pilot Projects
chemical_list: D000322:Adrenergic Agonists; D000336:Aerosols; D004837:Epinephrine
keywords: Anaphylaxis; Epinephrine; Inhalation; Mixed-effects modeling; Pharmacokinetics and pharmacodynamics