Clinical trial NCT01188577: Epinephrine Inhalation Aerosol USP, a HFA-MDI Study for Assessment of Pharmacokinetics
Official title: Epinephrine Inhalation Aerosol USP, an HFA-MDI CLINICAL STUDY-B2 FOR ASSESSMENT OF PHARMACOKINETICS (A Randomized, Evaluator-Blind, Single-Dose, Two Arm, Crossover, PK Study in Healthy Volunteers)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Asthma
Bronchospasm
Wheezing
Shortness of Breath
Keywords: asthma
bronchospasm
wheezing
shortness of breath
Lead sponsor: Amphastar Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2010-08-25
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study examines the pharmacokinetic profile of Armstrong's proposed Epinephrine Inhalation Aerosol USP, an HFA-MDI (E004), using a stable isotope deuterium-labeled epinephrine (epinephrine-d3) to differentiate the administered drug from the endogenous epinephrine, in healthy male and female adult volunteers. The current study is designed for a more thorough evaluation of the E004 Pharmacokinetics. Safety of E004 will also be evaluated, under augmented dose conditions.

Detailed description: E004 is formulated with epinephrine free base as the active ingredient, and hydrofluoroalkane (HFA-134a) as the propellant.

In order to differentiate the inhaled epinephrine from the fluctuating background of endogenous epinephrine 1, a stable-isotope deuterium (2H) labeled epinephrine (epinephrine-d3) preparation will be used to formulate E004 inhalers, denoted as E004-d3. PK of E004 at 125 mcg of epinephrine-d3 per inhalation, will be compared to that of the currently marketed, non-labeled, Epinephrine-CFC MDI as the Reference Control (220 mcg per inhalation).

This study is a randomized, evaluator-blind, single dose, two-arm, crossover, PK study, to be conducted in \~18 healthy, male and female, adult volunteers. PK will be studied using E004-d3 at 125 mcg per inhalation (Arm T). A currently marketed, non-labeled, Epinephrine CFC-MDI will be used as a Reference Control (Arm C).

Eligibility criteria: Inclusion Criteria:

* Generally healthy at screening;
* No clinically significant respiratory, cardiovascular and other systemic or organic illnesses;
* Body weight ≥ 50 kg for men and ≥ 45 kg for women,
* Sitting blood pressure ≤ 135/90 mm Hg;
* Demonstrating negative HIV, HBsAg and HCV-Ab screen tests;
* Women of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control;
* Properly consented
* Other criteria apply

Exclusion Criteria:

* A smoking history of ≥10 pack-years, or having smoked within 6 months;
* Upper respiratory tract infections within 2 wk, or lower respiratory tract infection within 4 wk, prior to Screening;
* Any current or recent respiratory conditions that might significantly affect pharmacodynamic response to the study drugs;
* Known intolerance or hypersensitivity to the study MDI ingredients;
* Having been on other investigational studies, or donated blood, in the last 30 days;
* Other Criteria Apply

Primary outcomes:
measure: Baseline Concentration (C0) of Total Epinephrine
timeFrame: 0 to 30 minutes prior to dosing
measure: Peak Concentration (Cmax) of Total Epinephrine From Time Zero to 6 Hours Post-dose
timeFrame: Pre-dose to 6 hours post-dose
measure: Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine
timeFrame: Pre-dose to 6 hours post-dose
measure: Time to Reach Peak Concentration (Tmax) for Total Epinephrine
timeFrame: Pre-dose to 6 hours post-dose
measure: Half-life (t1/2) of Total Epinephrine
timeFrame: Pre-dose to 6 hours post-dose
measure: Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose
timeFrame: Pre-dose to 6 hours post-dose
Secondary outcomes:
Other outcomes:
Locations:
city: Cypress
country: United States
facility: Amphastar Site 0035
state: California
Study officials:
affiliation: Amphastar Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Pinnas JL, Schachtel BP, Chen TM, Roseberry HR, Thoden WR. Inhaled epinephrine and oral theophylline-ephedrine in the treatment of asthma. J Clin Pharmacol. 1991 Mar;31(3):243-7. doi: 10.1002/j.1552-4604.1991.tb04969.x.
citation: Hendeles L, Marshik PL, Ahrens R, Kifle Y, Shuster J. Response to nonprescription epinephrine inhaler during nocturnal asthma. Ann Allergy Asthma Immunol. 2005 Dec;95(6):530-4. doi: 10.1016/S1081-1206(10)61014-9.
citation: Warren JB, Doble N, Dalton N, Ewan PW. Systemic absorption of inhaled epinephrine. Clin Pharmacol Ther. 1986 Dec;40(6):673-8. doi: 10.1038/clpt.1986.243.
citation: Cripps A, Riebe M, Schulze M, Woodhouse R. Pharmaceutical transition to non-CFC pressurized metered dose inhalers. Respir Med. 2000 Jun;94 Suppl B:S3-9.
citation: Dickinson BD, Altman RD, Deitchman SD, Champion HC. Safety of over-the-counter inhalers for asthma: report of the council on scientific affairs. Chest. 2000 Aug;118(2):522-6. doi: 10.1378/chest.118.2.522.
citation: Simons FE, Gu X, Johnston LM, Simons KJ. Can epinephrine inhalations be substituted for epinephrine injection in children at risk for systemic anaphylaxis? Pediatrics. 2000 Nov;106(5):1040-4. doi: 10.1542/peds.106.5.1040.
citation: Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol. 1999 Feb;77(2):79-88.
citation: Bondesson E, Friberg K, Soliman S, Lofdahl CG. Safety and efficacy of a high cumulative dose of salbutamol inhaled via Turbuhaler or via a pressurized metered-dose inhaler in patients with asthma. Respir Med. 1998 Feb;92(2):325-30. doi: 10.1016/s0954-6111(98)90116-0.
citation: Kerwin EM, Marrs T, Luo MZ, Zhang JY. 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.