Asthma, Bronchospasm, Shortness of Breath, Wheezing
Conditions
Keywords
asthma, bronchospasm, wheezing, shortness of breath
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).
Interventions
DRUGEpinephrine Inhalation Aerosol, HFA
10 inhalations of epinephrine inhalation aerosol, 125 mcg/inhalation
Epinephrine Inhalation Aerosol, 220 mcg/ inhalation, 10 inhalations
Sponsors
Amphastar Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from a specialty clinic in Cypress, CA between 08/19/2010 and 09/09/2010.
Pre-assignment details
A total of 35 subjects were screened, 23 subjects passed screening, consented and were randomized for participation in the study.
Participants by arm
| Arm | Count |
|---|---|
| C, T 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. | 11 |
| T, C 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. | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | C, T | T, C | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 12 Participants | 22 Participants |
| Age, Continuous | 22.8 Years STANDARD_DEVIATION 2.99 | 24.8 Years STANDARD_DEVIATION 2.93 | 23.8 Years STANDARD_DEVIATION 3.05 |
| Region of Enrollment United States | 11 participants | 12 participants | 23 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 23 | 2 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment T | Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine | 8498 pg*min/mL | Standard Deviation 5213 |
| Treatment C | Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) for Total Epinephrine | 6191 pg*min/mL | Standard Deviation 4108 |
Primary
Baseline Concentration (C0) of Total Epinephrine
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment T | Baseline Concentration (C0) of Total Epinephrine | 2.6 pg/mL | Standard Deviation 8.7 |
| Treatment C | Baseline Concentration (C0) of Total Epinephrine | 4.3 pg/mL | Standard Deviation 16.7 |
Primary
Concentration vs. Time for Total Epinephrine From Time Zero 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.
Time frame: Pre-dose to 6 hours post-dose
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 0 min (Baseline) | 2.6 pg/mL | Standard Deviation 8.7 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 25 min post-dose | 10.9 pg/mL | Standard Deviation 19.9 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 10 min post-dose | 118.3 pg/mL | Standard Deviation 65.8 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 30 min post-dose | 10.5 pg/mL | Standard Deviation 16.1 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 5 min post-dose | 379.4 pg/mL | Standard Deviation 203 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 45 min post-dose | 10.5 pg/mL | Standard Deviation 22.5 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 12.5 min post-dose | 75.6 pg/mL | Standard Deviation 42.2 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 2 min post-dose | 861.5 pg/mL | Standard Deviation 528.2 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 90 min post-dose | 3.5 pg/mL | Standard Deviation 9.4 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 15 min post-dose | 46.8 pg/mL | Standard Deviation 41.7 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 120 min post-dose | 6.5 pg/mL | Standard Deviation 13.2 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 7.5 min post-dose | 186.6 pg/mL | Standard Deviation 97.7 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 240 min post-dose | 16.1 pg/mL | Standard Deviation 23.8 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 20 min post-dose | 22.9 pg/mL | Standard Deviation 21.3 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 360 min post-dose | 17.1 pg/mL | Standard Deviation 23.9 |
| Treatment T | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 60 min post-dose | 8.7 pg/mL | Standard Deviation 13.9 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 360 min post-dose | 17.2 pg/mL | Standard Deviation 20.4 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 0 min (Baseline) | 4.3 pg/mL | Standard Deviation 16.7 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 2 min post-dose | 189.0 pg/mL | Standard Deviation 123.3 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 5 min post-dose | 99.1 pg/mL | Standard Deviation 67 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 7.5 min post-dose | 48.8 pg/mL | Standard Deviation 30 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 10 min post-dose | 39.7 pg/mL | Standard Deviation 22.9 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 12.5 min post-dose | 33.9 pg/mL | Standard Deviation 21.4 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 15 min post-dose | 32.0 pg/mL | Standard Deviation 23.3 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 20 min post-dose | 30.1 pg/mL | Standard Deviation 19.8 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 25 min post-dose | 20.3 pg/mL | Standard Deviation 17.9 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 30 min post-dose | 17.7 pg/mL | Standard Deviation 19.4 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 45 min post-dose | 19.8 pg/mL | Standard Deviation 21.2 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 60 min post-dose | 13.2 pg/mL | Standard Deviation 14.5 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 90 min post-dose | 11.2 pg/mL | Standard Deviation 18.2 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 120 min post-dose | 6.9 pg/mL | Standard Deviation 12 |
| Treatment C | Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | 240 min post-dose | 17.7 pg/mL | Standard Deviation 17.6 |
Primary
Half-life (t1/2) of Total Epinephrine
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Treatment T | Half-life (t1/2) of Total Epinephrine | 145.9 min |
| Treatment C | Half-life (t1/2) of Total Epinephrine | 289.8 min |
Primary
Peak Concentration (Cmax) of Total Epinephrine From Time Zero 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.
Time frame: Pre-dose to 6 hours post-dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment T | Peak Concentration (Cmax) of Total Epinephrine From Time Zero to 6 Hours Post-dose | 862 pg/mL | Standard Deviation 527 |
| Treatment C | Peak Concentration (Cmax) of Total Epinephrine From Time Zero to 6 Hours Post-dose | 190 pg/mL | Standard Deviation 119 |
Primary
Time to Reach Peak Concentration (Tmax) for Total Epinephrine
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment T | Time to Reach Peak Concentration (Tmax) for Total Epinephrine | 2.3 min | Standard Deviation 1.7 |
| Treatment C | Time to Reach Peak Concentration (Tmax) for Total Epinephrine | 3.4 min | Standard Deviation 4.3 |