A Study to Compare the Pharmacokinetics (PK) of Salbutamol Administered Via Metered Dose Inhalers (MDI) Containing Propellants HFA-152A (Test) or HFA-134A (Reference) in Healthy Participants Aged 18 to 55 Inclusive

GlaxoSmithKline60 enrolled

Overview

The primary objective of the study is to characterize the PK of single doses of salbutamol in healthy participants delivered via an MDI containing propellant HFA-152a (test), and to compare with an MDI containing propellant HFA-134a (reference).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Asthma Healthy Participants

Interventions

Salbutamol HFA-152aDRUG

100 µg (ex-valve), given at 20-second intervals.

Salbutamol HFA-134aDRUG

100 µg (ex-valve), given at 20-second intervals.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Sex: male or female; females may be of childbearing potential, of nonchild bearing potential, or postmenopausal. 2. Age: 18 to 55 years inclusive. 3. Weight: 45 to 110 kg inclusive 4. Status: healthy participants. 5. Females must not be pregnant or lactating. 6. All prescribed medication must have been stopped at least 30 days prior to admission to the clinical research center based on investigator judgment. An exception is made for hormonal contraceptives, which may be used throughout the study. 7. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John's wort) must have been stopped at least 14 days prior to admission to the clinical research center based on investigator judgment. An exception is made for acetaminophen, which is allowed up to admission to the clinical research center. 8. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to screening, and from 48 hours (2 days) prior to admission until discharge from the clinical research center. 9. Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to admission until discharge from the clinical research center. 10. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, ECG, and vital signs, as judged by the investigator. 11. Serum potassium and serum glucose levels within reference ranges of the clinical research center. 12. Willing and able to sign the informed consent form. 13. Spirometry at screening demonstrating forced expiratory volume ≥80% predicted. Exclusion Criteria: 1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs. 2. History or presence of any form of asthma, including childhood asthma and exercise induced asthma. 3. At screening, systolic blood pressure \<90 mmHg or \>140 mmHg, or diastolic blood pressure \<50 mmHg or \>90 mmHg. 4. History of pathological tachycardia, or a pulse rate \> 85 beats per minute (bpm) at screening or Day-1. 5. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. 6. Breast cancer within the past 10 years. 7. A QTcF value of \>450 msec at screening based on a triplicate measurement taken at a single timepoint. 8. Vaccine(s) within 2 weeks prior to admission, or plans to receive such vaccines during the study. 9. Donation or loss of more than 450 mL of blood within 60 days prior to (the first) drug administration. Donation or loss of more than 1.5 L of blood (for male participants) or more than 1.0 L of blood (for female participants) in the 10 months prior to (the first) drug administration in the current study. 10. Participation in a drug study within 30 days prior to (the first) drug administration in the current study. Participation in 4 or more other drug studies in the 12 months prior to (the first) drug administration in the current study. 11. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 12. Presence of hepatitis B surface antigen at screening or within 3 months prior to first dose of study intervention. 13. Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention. NOTE: Participants with positive hepatitis C antibody test result due to prior resolved disease can be enrolled if a confirmatory negative hepatitis C RNA test is obtained. 14. Positive pre-study drug/alcohol screen, including tetrahydrocannabinol. 15. Positive HIV antibody test. 16. Cotinine levels indicative of smoking or history or use of tobacco- or nicotine containing products within 6 months prior to screening. Assessment as ineligible by the investigator based on the results of the clinical laboratory tests or other assessments. 17. Average intake of more than 24 units of alcohol per week: 1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits. 18. Regular use of known drugs of abuse, including tetrahydrocannabinol. 19. Use of combustible tobacco products, and non-combustible nicotine delivery systems, inclusive of cigarettes, cigars, pipes, and materials used to "vape" within 6 months prior to screening. 20. Use of any products intended to treat medical conditions that are not approved by the governing health authority in a given country or region (for example, herbal medicine, health supplements, traditional medicine, homeopathic remedies, etc.). 21. Impairment which would prevent the correct and consistent use of an MDI, as determined by the investigator/delegate.

Locations (1)

GSK Investigational Site

Groningen, Netherlands

Outcomes

Primary Outcomes

Cohort 1: Area Under the Plasma Concentration-time Curve up to 30 Minutes Post- Dose (AUC[0-30])

Blood samples were collected for the analysis of Pharmacokinetic (PK) parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20 and 30 minutes post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-infinity])

Blood samples were collected for the analysis of Pharmacokinetic (PK) parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20, 30, 45 minutes post-dose and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 1: Maximum Observed Plasma Concentration (Cmax)

Blood samples were collected for the analysis of Pharmacokinetic (PK) parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20, 30, and 45 minutes post-dose and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 2: Area Under the Plasma Concentration-time Curve up to 30 Minutes Post- Dose (AUC[0-30])

Blood samples were collected for the analysis of Pharmacokinetic (PK) parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20 and 30 minutes post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 2: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-infinity])

Blood samples were collected for the analysis of Pharmacokinetic (PK) parameters.

Data from ClinicalTrials.gov

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Secondary Outcomes

Cohort 1: Time to Reach Cmax (Tmax)

Blood samples were collected for the analysis of PK parameters.

Cohort 1: Apparent Terminal Phase Half-life (t1/2)

Blood samples were collected for the analysis of PK parameters.

Cohort 1: Area Under the Plasma Concentration-time Curve up to Last Time With Concentrations Above the Lower Limit of Quantification (LLOQ) (AUC[0-last])

Blood samples were collected for the analysis of PK parameters.

Cohort 1-Intra-Participant Variability of AUC (0-30min)

Blood samples were collected for the analysis of PK parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20 and 30 minutes post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 1: Intra Participant Variability of AUC (0-infinity)

Blood samples were collected for the analysis of PK parameters.

Cohort 1: Intra Participant Variability of AUC(0-last)

Blood samples were collected for the analysis of PK parameters.

Cohort 1: Intra Participant Variability of Cmax

Blood samples were collected for the analysis of PK parameters.

Cohort 1: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose, results in death; was life threatening; required hospitalization or prolongation of existing hospitalization; resulted in disability/incapacity; was a congenital anomaly/birth defect, abnormal pregnancy outcomes. SAEs are subset of AEs. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.

Time frame: Up to 46 days [From ICF signing (Day -28) until telephonic follow-up (Day 18)]

Cohort 1: Absolute Values for 12 Lead Electrocardiogram (ECGs) Recording of Heart Rate (HR)

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the HR and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 1: Absolute Values for 12 Lead ECGs Recording of QT Interval Corrected Using Fridericia's Formula (QTcF) Intervals

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the QTcF Interval and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 1: Change From Baseline (CFB) for Post-dose 12 Lead ECGs Recording of HR

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated HR and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 1: Change From Baseline (CFB) for Post-dose 12 Lead ECGs Recording of QTcF Intervals

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the QTcF Interval and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameters: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelet Count

Blood samples were collected for analyzing absolute values of Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelet count. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameter: Erythrocytes

Blood samples were collected for analyzing absolute values of Erythrocytes. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameter: Mean Corpuscular Volume (MCV)

Blood samples were collected for analyzing absolute values of Mean Corpuscular Volume (MCV). Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameter: Mean Corpuscular Hemoglobin (MCH)

Blood samples were collected for analyzing absolute values of Mean corpuscular hemoglobin (MCH). Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameter: Hemoglobin

Blood samples were collected for analyzing absolute values of Hemoglobin. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Hematology Parameter: Hematocrit

Blood samples were collected for analyzing absolute values of Hematocrit. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Clinical Chemistry Parameters, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Creatine Phosphokinase (CPK)

Blood samples were collected for analyzing absolute values of Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Aspartate aminotransferase (AST) and Creatine Phosphokinase (CPK). Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values of Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Total Protein and Creatinine

Blood samples were collected for analyzing absolute values of direct bilirubin, total bilirubin, total protein and Creatinine. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values for Chemistry Parameters: Calcium, Sodium, Urea Nitrogen

Blood samples were collected for analyzing absolute values of Calcium, Sodium and Urea Nitrogen. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 1: Absolute Values for Chemistry Parameter: Glucose and Potassium

Blood samples were collected for analyzing absolute values of glucose and potassium

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 1.5, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]

Cohort 1: Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

SBP and DBP measurements were assessed with a completely automated device after the participant has been resting for at least 5 minutes in the supine position. Manual techniques were used only if an automated device was not available.

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]

Cohort 1: Absolute Values of Pulse Rate (PR)

Pulse rate measurements were assessed with a completely automated device after the participant has been resting for at least 5 minutes in the supine position. Manual techniques were used only if an automated device was not available.

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]

Cohort 2: Time to Reach Cmax (Tmax)

Blood samples were collected for the analysis of PK parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20, 30, and 45 minutes post-dose and at 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 [ Period 3] and Day 10 [Period 4]

Cohort 2: Apparent Terminal Phase Half-life (t1/2)

Blood samples were collected for the analysis of PK parameters.

Cohort 2: Area Under the Plasma Concentration-time Curve up to Last Time With Concentrations Above the Lower Limit of Quantification (LLOQ) (AUC[0-last])

Blood samples were collected for the analysis of PK parameters.

Cohort 2-Intra-Participant Variability of AUC (0-30min)

Blood samples were collected for the analysis of PK parameters.

Time frame: At pre-dose, 3, 5, 10, 15, 20 and 30 minutes post-dose on Day 1 (Period 1), Day 4 (Period 2), Day 7 (Period 3) and Day 10 (Period 4)

Cohort 2: Intra Participant Variability of AUC (0-infinity)

Blood samples were collected for the analysis of PK parameters.

Cohort 2: Intra Participant Variability of AUC (0-last)

Blood samples were collected for the analysis of PK parameters.

Cohort 2: Intra Participant Variability of Cmax

Blood samples were collected for the analysis of PK parameters.

Cohort 2: Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time frame: Up to 46 days [From ICF signing (Day -28) until telephonic follow-up (Day 18)]

Cohort 2: Absolute Values for 12 Lead Electrocardiogram (ECGs) Recording of Heart Rate (HR)

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the HR and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 2: Absolute Values for 12 Lead ECGs Recording of QTcF Intervals

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the QTcF Interval and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 2: Change From Baseline (CFB) for Post-dose 12 Lead ECGs Recording of HR

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated HR and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 2: Change From Baseline (CFB) for Post-dose 12 Lead ECGs Recording of QTcF Intervals

A standard 12 lead ECG was obtained using an ECG machine that automatically calculated the QTcF Interval and were measured after resting for at least 5 minutes in the supine position.

Time frame: Baseline (pre-dose) and post-dose at 30 minutes on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3], Day 10 [Period 4] and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameters: Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelet Count

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameter: Erythrocytes

Blood samples were collected for analyzing absolute values of Erythrocytes. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameter: Mean Corpuscular Volume (MCV)

Blood samples were collected for analyzing absolute values of Mean Corpuscular Volume (MCV). Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameter: Mean Corpuscular Hemoglobin (MCH)

Blood samples were collected for analyzing absolute values of Mean corpuscular hemoglobin (MCH). Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameter: Hemoglobin

Blood samples were collected for analyzing absolute values of Hemoglobin. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Hematology Parameter: Hematocrit

Blood samples were collected for analyzing absolute values of Hematocrit. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Clinical Chemistry Parameters, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Creatine Phosphokinase (CPK)

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values of Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin, Total Protein and Creatinine

Blood samples were collected for analyzing absolute values of direct bilirubin, total bilirubin, total protein and Creatinine. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values for Chemistry Parameters: Calcium, Sodium, Urea Nitrogen

Blood samples were collected for analyzing absolute values of Calcium, Sodium and Urea Nitrogen. Baseline is defined as the latest non-missing pre-dose value

Time frame: Baseline (Day -1) and Day 11 (Discharge)

Cohort 2: Absolute Values for Chemistry Parameter: Glucose and Potassium

Blood samples were collected for analyzing absolute values of glucose and potassium

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 1.5, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]

Cohort 2: Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]

Cohort 2: Absolute Values of Pulse Rate (PR)

Time frame: Baseline (Pre-dose) and Post-dose at 15, 30 minutes and 1, 2 and 4 hours on Day 1 [Period 1], Day 4 [Period 2], Day 7 [Period 3] and Day 10 [ Period 4]