Study of Drug Exposure in Systemic Circulation of Primatene Mist by Oral Inhalation, Versus Epinephrine Injection by Intramuscular Injection and ProAir by Oral Inhalation in Healthy Individuals

Study of Drug Exposure in Systemic Circulation of Primatene Mist (0.25mg) by Oral Inhalation, Versus Epinephrine Injection (0.30mg) by Intramuscular Injection and ProAir (0.18mg) by Oral Inhalation in Healthy Individuals: A Randomized, Safety Evaluator-blind, Three-Treatment, Crossover, Fasting Study

To assess the drug exposure profile in systemic circulation of Primatene Mist by inhalation, versus Epinephrine by intramuscular injection, and ProAir HFA by inhalation in healthy adults.

Study Overview

• Status: Completed
• Conditions: Asthma; Pharmacokinetics; Anaphylaxis; Epinephrine; Albuterol
• Intervention / Treatment: Combination product: Epinephrine (0.125 mg/inhalation); Combination product: Epinephrine Injection Auto-Injector (0.3mg/0.3mL); Combination product: Albuterol Sulfate (0.09 mg/inhalation)

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Cypress, California, United States, 90630
      • Amphastar Study Site 0035

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Agree to participate; understand and sign informed consent;
• Male and female adults, aged 18 to 50 years, inclusive at Screening;
• Generally healthy and medically stable, with no clinically significant abnormalities based on physical examination and laboratory tests as determined by the Investigators;
• Have good venous access;
• Have normal resting blood pressure and normal heart rate (HR) without history of syncope; a subject with out of range blood pressure may be enrolled in the study at the discretion of the Principal Investigator;
• Have a body mass index (BMI) of 18.0 - 30.0 kg/m^2;
• Female candidates must be >1 year post-menopausal or practicing a clinically acceptable form of birth control and confirmed by negative urine or serum pregnancy test at Screening;
• Negative HIV-Ab, HBs-Ag and HCV-Ab;
• Negative alcohol test (urine or breathalyzer);
• Negative drug screening results;
• Currently non-smoker; have not used any tobacco products for at least three (3) months prior to Screening; and
• Demonstrate proficiency in the use of MDI and a consistent inhalation time >2.0 seconds after training, for at least three (3) times, with a maximum of 5 attempts.

Exclusion Criteria:

• Concurrent clinically significant cardiovascular, hematological, renal, neurologic, hepatic, endocrine, psychiatric, or malignant diseases.
• Known intolerance or hypersensitivity to any component of the study drugs (i.e., Epinephrine, Albuterol Sulfate or any sympathomimetic drugs, HFA-134a, thymol, ethanol, ascorbic acid, nitric acid, and hydrochloric acid).
• Upper or lower respiratory tract infection, or other systemic infection within 6 weeks prior to Screening;
• Clinically significant abnormalities in the screening/baseline ECG; prolonged corrected QT interval (QTcF) on ECG: men >450ms, women: >470ms; single or multiple premature ventricular contractions (PVC);
• Abnormal thyroid function test (if TSH is out of range, refer to T3/T4 for thyroid function assessment);
• Subject has been on other investigational drug/device studies within 30 days of Screening Visit or planned participation in another investigational drug trial at any time during this trial;
• Women who are pregnant or lactating or planning a pregnancy during the study period;
• Subject has donated or lost > 500 mL of blood within 3 months of Screening;
• Evidence of alcohol or drug abuse or dependency within 6 months prior to screening; or
• Use of any of the prohibited drugs without appropriate washout.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Primatene Mist, E004; Participants who dosed with Primatene Mist.	Combination product: Epinephrine (0.125 mg/inhalation); Participants will self-administer 2 inhalations of Epinephrine (0.125 mg/inhalation) for a total dosage of 0.25 mg.; Other Names: Primatene Mist
Active Comparator: Epinephrine Injection Auto-Injector (Generic of EpiPen); Participants who were dosed with an Epinephrine Injection Auto-Injector.	Combination product: Epinephrine Injection Auto-Injector (0.3mg/0.3mL); Participants will receive an intramuscular injection of Epinephrine via Auto-Injector (0.30 mg of epinephrine solution in 0.30 mL). The 0.30 mL dose will be given perpendicularly as a single deep intramuscular injection into the anterolateral aspect of the thigh.; Other Names: Generic of EpiPen
Active Comparator: Albuterol HFA; Participants who dosed with Albuterol HFA.	Combination product: Albuterol Sulfate (0.09 mg/inhalation); Participants will self-administer 2 inhalations of Albuterol Sulfate (0.09 mg/inhalation) for a total dosage of 0.18 mg.; Other Names: Albuterol HFA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C[Max], Maximum Plasma Concentration of Albuterol or Epinephrine	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine. C[max] will be obtained directly from the plot of PK curve.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.
AUC(0-tm)_TOT, Area Under the Curve (AUC) of Total (Exogenous and Endogenous, if Available) Active Product Ingredient (API) From Time 0 to Time (tm)	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine. AUC(0-tm)_TOT will be calculated with the trapezoid method. Time tm is defined as the time after C[max] is reached where API concentration is reduced to the levels of the same day baseline.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.
AUC(0-tm)_DE, Area Under the Curve (AUC) of Exogenous Active Product Ingredient (API) From Time 0 to Time (tm)	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine. AUC(0-tm)_DE will be calculated with the trapezoid method. Time tm is defined as the time after C[max] is reached where API concentration is reduced to the levels of the same day baseline.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.
AUC(0-inf), Area Under the Curve (AUC) of Albuterol or Epinephrine From Time 0 to Infinity	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine. AUC(0-inf) will be calculated with the extrapolation method.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
t[Max], Time at Which Maximum Plasma Concentration of Albuterol or Epinephrine is Observed	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine. t[max] will be obtained directly from the plot of PK curve when the maximum concentration is observed.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.
t[1/2], Terminal Elimination Half-life of Albuterol or Epinephrine	Pharmacokinetic (PK) blood samples will be collected starting 30 minutes before dose and until 24 hours after dose. Plasma will be isolated for analyzing the concentrations of Albuterol and Epinephrine.	Samples were drawn at 30 minutes pre-dose and at 1, 2, 3, 5, 7, 9, 12, 15, 18, 21, 25, 30, 40, 50, 60, 70, 80, 90, 120 minutes, 4, 6, 8, 12, 18, and 24 hours post-dose.

Collaborators and Investigators

• Sponsor: Amphastar Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2019
• Primary Completion (Actual): December 20, 2019
• Study Completion (Actual): December 23, 2019

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 19, 2019
• First Posted (Actual): December 23, 2019

Study Record Updates

• Last Update Posted (Actual): March 30, 2021
• Last Update Submitted That Met QC Criteria: March 4, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Respiration Disorders; Hypersensitivity, Immediate; Hypersensitivity; Respiratory Aspiration; Anaphylaxis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Albuterol; Epinephrine; Racepinephrine; Epinephryl borate
• Other Study ID Numbers: API-E004-CL-I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Access to patient level data and supporting clinical documents may be requested by qualified researchers. Requests will be reviewed on the basis of scientific merit. Patient data will be de-identified to protect the privacy of trial patients in line with applicable laws and regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No