Albuterol, Anaphylaxis, Asthma, Epinephrine, Pharmacokinetics
Conditions
Brief summary
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.
Interventions
COMBINATION_PRODUCTEpinephrine (0.125 mg/inhalation)
Participants will self-administer 2 inhalations of Epinephrine (0.125 mg/inhalation) for a total dosage of 0.25 mg.
COMBINATION_PRODUCTEpinephrine 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.
COMBINATION_PRODUCTAlbuterol 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.
Sponsors
Amphastar Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| C[Max], Maximum Plasma Concentration of Albuterol or 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. | 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. |
| 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) | 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. | 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. |
| AUC(0-tm)_DE, Area Under the Curve (AUC) of Exogenous Active Product Ingredient (API) From Time 0 to Time (tm) | 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. | 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. |
| AUC(0-inf), Area Under the Curve (AUC) of Albuterol or Epinephrine From Time 0 to Infinity | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t[Max], Time at Which Maximum Plasma Concentration of Albuterol or Epinephrine 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. | 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. |
| t[1/2], Terminal Elimination Half-life of Albuterol or 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. | 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. |
Countries
United States
Participant flow
Pre-assignment details
Participants were randomized to receive all 3 treatments over 3 treatment periods in a crossover design.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All participants who have been randomized. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Washout Period 1 (2-7 Days) | Withdrawal by Subject | 0 | 0 | 1 |
| Washout Period 2 (2-7 Days) | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 7.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African-American | 10 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Race/Ethnicity, Customized White | 13 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 26 | 0 / 28 |
| other Total, other adverse events | 3 / 27 | 1 / 26 | 2 / 28 |
| serious Total, serious adverse events | 0 / 27 | 0 / 26 | 0 / 28 |
Outcome results
Primary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | AUC(0-inf), Area Under the Curve (AUC) of Albuterol or Epinephrine From Time 0 to Infinity | 18.4 pg/mL x hr | Standard Deviation 3.6 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | AUC(0-inf), Area Under the Curve (AUC) of Albuterol or Epinephrine From Time 0 to Infinity | 411.4 pg/mL x hr | Standard Deviation 1.7 |
| Albuterol HFA | AUC(0-inf), Area Under the Curve (AUC) of Albuterol or Epinephrine From Time 0 to Infinity | 3650.4 pg/mL x hr | Standard Deviation 1.3 |
Primary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | AUC(0-tm)_DE, Area Under the Curve (AUC) of Exogenous Active Product Ingredient (API) From Time 0 to Time (tm) | 18.4 pg/mL x hr | Standard Deviation 3.6 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | AUC(0-tm)_DE, Area Under the Curve (AUC) of Exogenous Active Product Ingredient (API) From Time 0 to Time (tm) | 396.3 pg/mL x hr | Standard Deviation 1.6 |
| Albuterol HFA | AUC(0-tm)_DE, Area Under the Curve (AUC) of Exogenous Active Product Ingredient (API) From Time 0 to Time (tm) | 3332.3 pg/mL x hr | Standard Deviation 1.3 |
Primary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | 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) | 26.8 pg/mL x hr | Standard Deviation 3.1 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | 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) | 509.9 pg/mL x hr | Standard Deviation 1.5 |
| Albuterol HFA | 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) | 3332.3 pg/mL x hr | Standard Deviation 1.3 |
Primary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | C[Max], Maximum Plasma Concentration of Albuterol or Epinephrine | 240.8 pg/mL | Standard Deviation 2.4 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | C[Max], Maximum Plasma Concentration of Albuterol or Epinephrine | 704.8 pg/mL | Standard Deviation 1.8 |
| Albuterol HFA | C[Max], Maximum Plasma Concentration of Albuterol or Epinephrine | 599.8 pg/mL | Standard Deviation 1.7 |
Secondary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | t[1/2], Terminal Elimination Half-life of Albuterol or Epinephrine | 7.1 min | Standard Deviation 5.2 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | t[1/2], Terminal Elimination Half-life of Albuterol or Epinephrine | 138.8 min | Standard Deviation 4 |
| Albuterol HFA | t[1/2], Terminal Elimination Half-life of Albuterol or Epinephrine | 420.7 min | Standard Deviation 1.2 |
Secondary
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.
Time frame: 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.
Population: Per Protocol Population, defined as all subjects who have received all study medications and are evaluable for all treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Primatene Mist, E004 | t[Max], Time at Which Maximum Plasma Concentration of Albuterol or Epinephrine is Observed | 2.6 min | Standard Deviation 3 |
| Epinephrine Injection Auto-Injector (Generic of EpiPen) | t[Max], Time at Which Maximum Plasma Concentration of Albuterol or Epinephrine is Observed | 8.3 min | Standard Deviation 2.7 |
| Albuterol HFA | t[Max], Time at Which Maximum Plasma Concentration of Albuterol or Epinephrine is Observed | 21.8 min | Standard Deviation 3.1 |