Pharmacokinetic Study of Epinephrine Hydrofluoroalkane (Primatene MIST) Metered-Dose Inhaler

J Aerosol Med Pulm Drug Deliv. 2020 Oct;33(5):282-287. doi: 10.1089/jamp.2019.1577. Epub 2020 May 18.

Abstract

Background: Primatene® MIST CFC, an epinephrine metered-dose inhaler (MDI), was discontinued from the market owing to environmental concerns from its use of chlorofluorocarbon (CFC) propellant. As a result, a new epinephrine MDI was developed using hydrofluoroalkane (HFA) propellant. This article reports the pharmacokinetic (PK) profile of the newly Food and Drug Administration-approved epinephrine HFA MDI. Methods: A randomized, evaluator-blinded, active-controlled, single-dose, two-arm crossover study was conducted to evaluate the PK profile of epinephrine HFA (Primatene® MIST) and epinephrine CFC (Primatene® MIST CFC) in 23 healthy volunteers to characterize the epinephrine absorption extent and rate. The study was performed at a high dose of five times the normal dose to obtain measurable plasma epinephrine levels. Plasma epinephrine levels were measured and safety was assessed by adverse events (AEs), vital signs, clinical laboratory tests, and physical examinations. Results: Epinephrine HFA demonstrated a greater systemic drug exposure (greater area under the curve) than that of epinephrine CFC (∼37% higher). The Cmax occurred at ∼2 minutes and was significantly higher in the epinephrine HFA group (0.18 ng/mL) compared with the CFC version (0.046 ng/mL) at normal dose. Within 20 minutes, both groups demonstrated comparable plasma epinephrine levels. No clinically significant adverse effects were found to be associated with epinephrine HFA, even after an ultrahigh dose (i.e., 10 inhalations). Conclusions: The systemic exposure of epinephrine HFA was found to be higher for the first 20 minutes, and then comparable with epinephrine CFC. Minimal AEs were found in this study despite the very high 1250-2200 μg inhaled doses (i.e., 10 inhalations) used for PK characterization.

Trial registration: ClinicalTrials.gov NCT01188577.

Keywords: asthma; high dose; inhaled epinephrine; pharmacokinetic; systemic exposure.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adolescent
  • Adult
  • Aerosol Propellants / chemistry*
  • Area Under Curve
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / adverse effects
  • Bronchodilator Agents / pharmacokinetics
  • Chlorofluorocarbons / chemistry
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Epinephrine / administration & dosage*
  • Epinephrine / adverse effects
  • Epinephrine / pharmacokinetics
  • Female
  • Humans
  • Hydrocarbons, Fluorinated / chemistry*
  • Male
  • Metered Dose Inhalers
  • Single-Blind Method
  • Young Adult

Substances

  • Aerosol Propellants
  • Bronchodilator Agents
  • Chlorofluorocarbons
  • Hydrocarbons, Fluorinated
  • apaflurane
  • Epinephrine

Associated data

  • ClinicalTrials.gov/NCT01188577