Epinephrine Inhalation Aerosol USP, a HFA-MDI Study for Assessment of Pharmacokinetics

• Sponsor: Amphastar Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01188577
• Collaborator: (none)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 5
• Patients Per Site Per Month: 4.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Asthma; Bronchospasm; Wheezing; Shortness of Breath	Drug: Epinephrine Inhalation Aerosol, HFA; Drug: Epinephrine Inhalation Aerosol	Phase 1/Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Aug 1, 2010
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Epinephrine Inhalation Aerosol, HFA Experimental treatment of 10 inhalations of 125 mcg epinephrine base propelled by HFA 134a	Drug: Epinephrine Inhalation Aerosol, HFA; 10 inhalations of epinephrine inhalation aerosol, 125 mcg/inhalation; Other Names: HFA epinephrine inhalation aerosol, 125 mcg/inhalation
Active Comparator: Epinephrine Inhalation Aerosol, CFC Epinephrine Inhalation Aerosol, CFC propelled, 220 mcg/inhalation , 10 inhalations	Drug: Epinephrine Inhalation Aerosol; Epinephrine Inhalation Aerosol, 220 mcg/ inhalation, 10 inhalations; Other Names: Primatene Mist Epinephrine Inhalation Aerosol, USP

Outcome Measures

Primary Outcome Measures

1. Baseline Concentration (C0) of Total Epinephrine [0 to 30 minutes prior to dosing]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at Baseline (prior to dosing) in each treatment period following a specified washout period (3-14 days), and were analyzed using an established analysis method. Baseline concentration (C0) is the concentration of epinephrine measured in the plasma at this time point.

2. Peak Concentration (Cmax) of Total Epinephrine From Time Zero to 6 Hours Post-dose [Pre-dose to 6 hours post-dose]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Peak (maximum) concentration (Cmax) is the highest concentration of epinephrine measured in plasma during the treatment period.

3. Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine [Pre-dose to 6 hours post-dose]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Area under the curve from time zero to 6 hours post-dose (AUC[0-6]) was calculated using the trapezoidal rule.

4. Time to Reach Peak Concentration (Tmax) for Total Epinephrine [Pre-dose to 6 hours post-dose]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Tmax is the amount of time it takes for epinephrine to reach peak concentration in plasma during the treatment period.

5. Half-life (t1/2) of Total Epinephrine [Pre-dose to 6 hours post-dose]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Half-life (t1/2) is the amount of time it takes for epinephrine to decrease to half the peak concentration in plasma during the treatment period.

6. Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose [Pre-dose to 6 hours post-dose]

   Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Amphastar Site 0035	Cypress	California	United States	90630

Sponsors and Collaborators

• Amphastar Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Amphastar Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bondesson E, Friberg K, Soliman S, Löfdahl 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.
• 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.
• 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.
• 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.
• 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. Review.
• 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.
• 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.
• Warren JB, Doble N, Dalton N, Ewan PW. Systemic absorption of inhaled epinephrine. Clin Pharmacol Ther. 1986 Dec;40(6):673-8.

• Responsible Party: Amphastar Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01188577
• Other Study ID Numbers: API-E004-CL-B2
• First Posted: Aug 25, 2010
• Last Update Posted: Jul 25, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Amphastar Pharmaceuticals, Inc.: asthma; bronchospasm; wheezing; shortness of breath
• Additional relevant MeSH terms: Bronchial Spasm; Dyspnea; Respiratory Sounds; Epinephrine; Racepinephrine; Epinephryl borate

Study Results

Participant Flow

Recruitment Details	Participants were recruited from a specialty clinic in Cypress, CA between 08/19/2010 and 09/09/2010.
Pre-assignment Detail	A total of 35 subjects were screened, 23 subjects passed screening, consented and were randomized for participation in the study.

Arm/Group Title	C, T	T, C
Arm/Group Description	Subjects received one of the two treatments during each study visit, separated by a washout period of 3-14 days. Visit 1: Treatment C: Ten (10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min; Visit 2: Treatment T: Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min.	Subjects received one of the two treatments during each study visit, separated by a washout period of 3-14 days. Visit 1: Treatment T: Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min; Visit 2: Treatment C: Ten (10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min.
Period Title: Visit 1
STARTED	11	12
COMPLETED	11	12
NOT COMPLETED	0	0
Period Title: Visit 1
STARTED	11	12
COMPLETED	11	12
NOT COMPLETED	0	0
Period Title: Visit 1
STARTED	11	12
COMPLETED	11	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	C, T	T, C	Total
Arm/Group Description	Subjects received one of the two treatments during each study visit, separated by a washout period of 3-14 days. Visit 1: Treatment C: Ten (10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min; Visit 2: Treatment T: Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min.	Subjects received one of the two treatments during each study visit, separated by a washout period of 3-14 days. Visit 1: Treatment T: Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min; Visit 2: Treatment C: Ten (10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min.	Total of all reporting groups
Overall Participants	11	12	23
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	22.8 (2.99)	24.8 (2.93)	23.8 (3.05)
Age (Count of Participants)
<=18 years	1 9.1%	0 0%	1 4.3%
Between 18 and 65 years	10 90.9%	12 100%	22 95.7%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 18.2%	4 33.3%	6 26.1%
Male	9 81.8%	8 66.7%	17 73.9%
Region of Enrollment (participants) [Number]
United States	11 100%	12 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Baseline Concentration (C0) of Total Epinephrine
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at Baseline (prior to dosing) in each treatment period following a specified washout period (3-14 days), and were analyzed using an established analysis method. Baseline concentration (C0) is the concentration of epinephrine measured in the plasma at this time point.
Time Frame	0 to 30 minutes prior to dosing

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurement btwn 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
Mean (Standard Deviation) [pg/mL]	2.6 (8.7)	4.3 (16.7)

2. Primary Outcome

Title	Peak Concentration (Cmax) of Total Epinephrine From Time Zero to 6 Hours Post-dose
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Peak (maximum) concentration (Cmax) is the highest concentration of epinephrine measured in plasma during the treatment period.
Time Frame	Pre-dose to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurements btw 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
Mean (Standard Deviation) [pg/mL]	862 (527)	190 (119)

3. Primary Outcome

Title	Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Area under the curve from time zero to 6 hours post-dose (AUC[0-6]) was calculated using the trapezoidal rule.
Time Frame	Pre-dose to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurements btw 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
Mean (Standard Deviation) [pg*min/mL]	8498 (5213)	6191 (4108)

4. Primary Outcome

Title	Time to Reach Peak Concentration (Tmax) for Total Epinephrine
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Tmax is the amount of time it takes for epinephrine to reach peak concentration in plasma during the treatment period.
Time Frame	Pre-dose to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurements btw 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
Mean (Standard Deviation) [min]	2.3 (1.7)	3.4 (4.3)

5. Primary Outcome

Title	Half-life (t1/2) of Total Epinephrine
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Half-life (t1/2) is the amount of time it takes for epinephrine to decrease to half the peak concentration in plasma during the treatment period.
Time Frame	Pre-dose to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurements btw 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
Mean (Full Range) [min]	145.9	289.8

6. Primary Outcome

Title	Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose
Description	Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method.
Time Frame	Pre-dose to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Patients who: 1) have taken the valid pre-dose baseline PK sample 2) have correctly taken the randomized study drug treatment 3) have at least three of the four post-dose PK measurements btw 2 and 10 min post-dose available and 4) have a minimum of twelve of the fifteen post-dose PK measurements for the entire 6 hour post-dose PK sampling period.

Arm/Group Title	Treatment T	Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min	Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
Measure Participants	23	23
0 min (Baseline)	2.6 (8.7)	4.3 (16.7)
2 min post-dose	861.5 (528.2)	189.0 (123.3)
5 min post-dose	379.4 (203.0)	99.1 (67.0)
7.5 min post-dose	186.6 (97.7)	48.8 (30.0)
10 min post-dose	118.3 (65.8)	39.7 (22.9)
12.5 min post-dose	75.6 (42.2)	33.9 (21.4)
15 min post-dose	46.8 (41.7)	32.0 (23.3)
20 min post-dose	22.9 (21.3)	30.1 (19.8)
25 min post-dose	10.9 (19.9)	20.3 (17.9)
30 min post-dose	10.5 (16.1)	17.7 (19.4)
45 min post-dose	10.5 (22.5)	19.8 (21.2)
60 min post-dose	8.7 (13.9)	13.2 (14.5)
90 min post-dose	3.5 (9.4)	11.2 (18.2)
120 min post-dose	6.5 (13.2)	6.9 (12.0)
240 min post-dose	16.1 (23.8)	17.7 (17.6)
360 min post-dose	17.1 (23.9)	17.2 (20.4)

Adverse Events

Time Frame	Throughout entire study period
Arm/Group Title	Treatment T		Treatment C
Arm/Group Description	Ten (10) inhalations of E004 (125 mcg/inhalation), totaling 1.25 mg of epinephrine, in 5 min		Ten(10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation), totaling 2.20 mg of epinephrine, in 5 min
All Cause Mortality
	Treatment T		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment T		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Treatment T		Treatment C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		2/23 (8.7%)
Gastrointestinal disorders
Diarrhoea	1/23 (4.3%)	1	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/23 (0%)	0	1/23 (4.3%)	1
Viral Upper Respiratory Tract Infection	0/23 (0%)	0	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.