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

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.

Conflict of interest statement

Dr. E.M.K. served on advisory boards, speaker panels, consultants, or received travel reimbursement from Novartis, AstraZeneca, Amphastar, Forest, Pearl, Sunovion, Teva, Theravance, Mylan, GSK, Boehringer Ingelheim, and Cipla outside the submitted work. Dr. J.Y.Z., Dr. M.Z.L. and T.M. are employees of Amphastar Pharmaceuticals, Inc. at the time of study and article preparation.

Figures

FIG. 1.

Extrapolated plasma epinephrine concentration curves at normal dose: Peak plasma epinephrine concentration levels occurred at 2 minutes postdose, 180 pg/mL for Epi-HFA and 46 pg/mL for Epi-CFC, respectively. HFA, hydrofluoroalkane; CFC, chlorofluorocarbon.