Healthy
Conditions
Brief summary
This study was designed to assess the bioequivalence between the test products (Albuterol Sulfate Inhalation Aerosol 108 mcg Per Actuation) and the reference products (Proair HFA \[Albuterol Sulfate\] Inhalation Aerosol 90 mcg Per Actuation) in healthy volunteers under fasting conditions. The test product was considered bioequivalent to the reference product if the T/R ln-transformed AUC(0-t), AUC(0-inf), and Cmax were within 80.00-125.00% of those of the reference.
Detailed description
A single-dose, randomized, open-label, two-period, two-sequence, two-treatment, single-centre, crossover bioequivalence study was carried out under fasting conditions in healthy adults, aged 20-60 years. For each period, each subject received a single dose as equivalent to 180 mcg of albuterol of the study drugs according to the pre-determined randomization scheme. Each subject was drawn 22 times over the period of 24 hours. Plasma samples were collected and analyzed for albuterol concentrations by using LC-MS/MS. For each subject, there were 2 dosing periods separated by a 14-day washout period. During the study, standardized meals were provided to all subjects while institutionalized.
Interventions
MDI, 2 puffs, single dose, fasting
DRUGProair HFA (albuterol sulfate) Inhalation Aerosol 90 mcg per actuation
MDI, 2 puffs, single dose, fasting
Sponsors
Intech Biopharm Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male and female volunteers, aged 20-60, inclusive. 2. BMI of 18.0-30.0 kg/m², inclusive. The body weight should be over 50 kg, inclusive. (BMI will be calculated as weight in kilogram \[kg\]/height in meters² \[m²\]). 3. Healthy or Non Clinical Significant, according to the medical history, ECG, chest X-ray and physical examination as determined by the Principal Investigator/Sub-Investigator. 4. Systolic blood pressure between 90-139 mmHg, inclusive, and diastolic blood pressure between 50-90 mmHg, inclusive, and pulse rate between 50-100 bpm, inclusive and temperature between 35.0-37.4℃. 5. Screening laboratory values within reference range or NCS as determined by the Principal Investigator/Sub-Investigator. 6. Ability to comprehend and be informed of the nature of the study, as assessed by clinical staff. Capable of giving written informed consent prior to receiving any study medication. Must be able to communicate effectively with clinical staff. 7. Willing to fast for at least 14 hours and to consume standard meals. 8. Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements. 9. Agree not to have a tattoo, body piercing, or other any invasive procedure and blood donation until the end of the study. 10. Never-smokers; or former smokers who have smoked ≥ 100 cigarettes in their lifetime and have not consumed any tobacco or tobacco containing products for at least 12 months prior to screening. 11. Subjects who are non-asthmatic, defined as no clinical history of asthma, allergy or atopy. 12. Able to perform special breathing using nebulizer correctly as per the required standard. 13. Subjects must fulfill at least one of the following: * Be surgically sterile for a minimum of 6 months; * Post-menopausal for a minimum of 1 year; * Agree to avoid pregnancy and use medically acceptable method of contraception from screening day until 30 days after the study ends (last study procedure).
Exclusion criteria
1. Known history or presence of any clinically significant hepatic (e.g. active liver disease, hepatic impairment), renal/genitourinary (e.g. renal impairment), gastrointestinal, cardiovascular, cerebrovascular, pulmonary, endocrine (e.g. hypothyroidism), immunological, musculoskeletal (e.g. myopathy, rhabdomyolysis), neurological, psychiatric, dermatological, hematological disease, or any other medical conditions, unless determined as not clinically significant by the Principal Investigator/Sub-Investigator. 2. Presence of any clinically significant illness within 30 days prior to first dosing, as determined by the Principal Investigator/Sub-Investigator. 3. Presence of any significant physical or organ abnormality as determined by the Principal Investigator/Sub-Investigator. 4. A positive test result for any of the following: HIV, Hepatitis B surface antigen, Hepatitis C, drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, tetrahydrocannabinol), breath alcohol test. Positive pregnancy test for female subjects. 5. Known history or presence of: * Alcohol abuse within one year prior to first drug administration; * Drug abuse or dependence; * Hypersensitivity or idiosyncratic reaction to albuterol, its excipients, and/or related substances; * Allergy to standardized meal provided by site and/or presence of any dietary restrictions; 6. Intolerance to and/or difficulty in blood sampling through venipuncture. 7. Abnormal diet patterns (for any reason) during the 4 weeks preceding the study, including fasting, high protein diets etc. 8. Except for screening procedures, blood donation that results in blood loss of not more than 250 ml in the past 2 months prior to first dosing; blood loss of more than 250 ml within 3 months prior to first dosing. 9. Donation of plasma by plasmapheresis within 7 days prior to first drug administration. 10. Individuals who receives an investigational drug from 2 months prior to first drug administration. 11. Consumption of products containing caffeine/methylxanthines, poppy seeds and/or alcohol within 48 hours before dosing and products containing grapefruit and/or pomelo (shown to inhibit cytochrome P450 \[CYP\] 3A4 activity) within 10 days prior to first drug administration. 12. Use of any medication, including oral multivitamins, herbal and/or dietary supplements within 30 days prior to first drug administration (except topical agents without systemic absorption as determined by the Principal Investigator/Sub-Investigator). 13. Females taking oral or transdermal hormonal contraceptives within 30 days prior to first drug administration. 14. Females having used implanted, injected, intravaginal, or intrauterine hormonal contraceptive within 6 months prior to first drug administration. 15. Individuals having undergone any major surgery within 6 months prior to the start of the study, unless deemed otherwise by Principal Investigator/Sub-Investigator. 16. Using tobacco products, nicotine products (patches, gum etc.) within 6 months prior to first drug administration. 17. Lactating women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose | The maximal observed plasma concentration of Albuterol Sulfate. |
| AUC(0-t) | 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose | Area under the concentration time curve from time zero until the last measurable concentration or last sampling time t, whichever occurs first. |
| AUC(0-inf) | 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose | Area under the concentration time curve from time zero to infinity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 0-24 hours | Time when the maximal plasma concentration is observed. |
| Mean Residence Time (MRT) | 0-24 hours | Mean residence time (MRT) is calculated by the area under the first moment curve dividing by area under the concentration time curve. |
| T1/2 | 0-24 hours | Terminal elimination half-life, estimated as ln(2)/λ. |
| Kel(λ) | 0-24 hours | Terminal elimination rate constant, estimated by linear regression analysis of the terminal portion of the ln-concentration vs. time plot. |
Countries
Taiwan
Participant flow
Recruitment details
Eighty-four subjects were recruited and screened for the eligibility.
Pre-assignment details
Sixty eligible subjects were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Summary of Demographic Data and Baseline Characteristics for All Study Participants. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 31.9 years STANDARD_DEVIATION 7.4 |
| Body mass index (BMI) | 23.2 kg/m^2 STANDARD_DEVIATION 2.2 |
| Height | 167.8 cm STANDARD_DEVIATION 6.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 60 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 41 Participants |
| Weight | 65.5 kg STANDARD_DEVIATION 8.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 58 |
| other Total, other adverse events | 4 / 60 | 1 / 58 |
| serious Total, serious adverse events | 0 / 60 | 0 / 58 |
Outcome results
Primary
AUC(0-inf)
Area under the concentration time curve from time zero to infinity.
Time frame: 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | AUC(0-inf) | 5204.806 hr*pg/mL | Standard Deviation 1081.862 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | AUC(0-inf) | 5509.006 hr*pg/mL | Standard Deviation 1148.747 |
p-value: <0.000190% CI: [0.91, 0.975]ANOVA
Primary
AUC(0-t)
Area under the concentration time curve from time zero until the last measurable concentration or last sampling time t, whichever occurs first.
Time frame: 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | AUC(0-t) | 4806.319 hr*pg/mL | Standard Deviation 981.477 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | AUC(0-t) | 5090.449 hr*pg/mL | Standard Deviation 1053.602 |
p-value: <0.000190% CI: [0.909, 0.976]ANOVA
Primary
Cmax
The maximal observed plasma concentration of Albuterol Sulfate.
Time frame: 0 hour (pre-dose), as well as at 2, 5, 10, 15, 20, 30, 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post-dose
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | Cmax | 812.477 pg/mL | Standard Deviation 281.148 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | Cmax | 945.456 pg/mL | Standard Deviation 359.695 |
p-value: 0.032890% CI: [0.807, 0.922]ANOVA
Secondary
Kel(λ)
Terminal elimination rate constant, estimated by linear regression analysis of the terminal portion of the ln-concentration vs. time plot.
Time frame: 0-24 hours
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | Kel(λ) | 0.103 1/hr | Standard Deviation 0.019 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | Kel(λ) | 0.103 1/hr | Standard Deviation 0.021 |
Secondary
Mean Residence Time (MRT)
Mean residence time (MRT) is calculated by the area under the first moment curve dividing by area under the concentration time curve.
Time frame: 0-24 hours
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | Mean Residence Time (MRT) | 8.629 hr | Standard Deviation 1.202 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | Mean Residence Time (MRT) | 8.474 hr | Standard Deviation 1.455 |
Secondary
T1/2
Terminal elimination half-life, estimated as ln(2)/λ.
Time frame: 0-24 hours
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | T1/2 | 6.928 hr | Standard Deviation 1.165 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | T1/2 | 6.985 hr | Standard Deviation 1.357 |
Secondary
Tmax
Time when the maximal plasma concentration is observed.
Time frame: 0-24 hours
Population: R014, R040, R055, R058 had protocol issues including significantly delayed blood sampling and leakage of drug during dosing. R029 and R058 had pre-dose concentrations \> 5% of Cmax. Data of remaining 53 subjects was considered for pharmacokinetic and statistical analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol Sulfate Inhalation Aerosol | Tmax | 0.929 hr | Standard Deviation 1.089 |
| Proair HFA (Albuterol Sulfate) Inhalation Aerosol | Tmax | 0.514 hr | Standard Deviation 0.529 |