A Phase I, Randomized, Double-blind, Single-dose, Partial Replicate, 3-way Cross-over Study to Assess the Lung Exposure Bioequivalence of Budesonide, Glycopyrronium, and Formoterol Delivered by BGF MDI HFO Compared With BGF MDI HFA
Overview
- Phase
- Phase 1
- Intervention
- Treatment A (BGF MDI HFO with oral activated charcoal)
- Conditions
- Chronic Obstructive Pulmonary Disease
- Sponsor
- AstraZeneca
- Enrollment
- 108
- Locations
- 1
- Primary Endpoint
- Maximum Observed Plasma (Peak) Drug Concentration (Cmax )
- Status
- Completed
- Last Updated
- 8 months ago
Overview
Brief Summary
The study will assess the Pharmacokinetic (PK) and safety of BGF MDI [Budesonide/glycopyrronium/formoterol (BGF) metered dose inhaler (MDI)] formulated with 2 different propellants :Hydrofluoroolefin (HFO) and Hydrofluoroalkane (HFA) with oral activated charcoal in healthy subjects (male or female).
Detailed Description
This is a Phase I, randomized, double-blind, single-dose, single-center, partial-replicate, 3 way cross-over study. The study will comprise: * Screening period: up to 28 days prior to first dosing; * Three treatment periods : Subject will be resident in the Clinical Unit from the morning on the day before dosing with BGF MDI (Day 1 of Treatment Period 1), until 24 hours following the final dose (Day 2 of Treatment Period 3 a washout period of 3 to 7 days between each dose; * Follow-up: Within 3 to 7 days after the last administration of BGF MDI. Subjects will receive 3 single-dose treatments of BGF MDI \[Test formulation Treatment A (BGF MDI HFO); Reference formulation Treatment B (BGF MDI HFA)\] on Day 1 of each Treatment Period (1, 2, and 3) following an overnight fast of at least 8 hours. There will be a washout period of 3 to 7 days between each dose. Each subjects will be involved in the study for up to 55 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy non-smoking male and/or female subjects aged 18 - 60 years with suitable veins for cannulation or repeated venipuncture.
- •Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating, confirmed at screening.
- •Have a Body Mass Index (BMI) between 18 and 35 kg/m2 inclusive and weigh at least 50 kg and no more than 120 kg inclusive.
- •Subjects must have a Forced expiratory volume in the first second (FEV1) ≥ 80% of the predicted normal value and an FEV1/FVC (Forced vital capacity) \> 70% regarding age, height, and ethnicity at the screening visit.
- •Subjects must demonstrate proper inhalation technique and have the ability to properly use an MDI device after training.
- •Provision of signed and dated, written informed consent prior to any study specific procedures.
Exclusion Criteria
- •History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate.
- •History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of Investigational Medicinal Product (IMP).
- •History of narrow angle glaucoma not adequately treated and/or change in vision that may be relevant.
- •History of symptomatic prostatic hypertrophy or bladder neck obstruction/urinary retention.
- •Unresectable cancer that has not been in complete remission for at least 5 years.
- •Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results.
- •Any clinically significant abnormal findings in physical examination, or vital signs at screening.
- •Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening.
- •Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and HIV antibody.
Arms & Interventions
Treatment A: BGF MDI HFO 160/7.2/4.8 μg ex-actuator with oral activated charcoal
Subjects will receive Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability.
Intervention: Treatment A (BGF MDI HFO with oral activated charcoal)
Treatment A: BGF MDI HFO 160/7.2/4.8 μg ex-actuator with oral activated charcoal
Subjects will receive Test formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability.
Intervention: Treatment B (BGF MDI HFA with oral activated charcoal)
Treatment B: BGF MDI HFA 160/7.2/4.8 μg ex-actuator with oral activated charcoal
Subjects will receive Reference formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability.
Intervention: Treatment A (BGF MDI HFO with oral activated charcoal)
Treatment B: BGF MDI HFA 160/7.2/4.8 μg ex-actuator with oral activated charcoal
Subjects will receive Reference formulation in 1 of 3 possible treatment sequences: ABB, BAB, or BBA. The reference formulation will be administered during 2 of the 3 treatment periods in order to estimate intra-subject variability.
Intervention: Treatment B (BGF MDI HFA with oral activated charcoal)
Outcomes
Primary Outcomes
Maximum Observed Plasma (Peak) Drug Concentration (Cmax )
Time Frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hours (h), 2 h, 4 h, 8 h, 12h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Bioequivalence (Cmax) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Area Under Plasma Concentration Time Curve From Zero to Infinity (AUCinf)
Time Frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Bioequivalence (AUCinf) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Area Under the Plasma Concentration Curve From Zero to the Last Quantifiable Concentration (AUClast)
Time Frame: Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days)
Bioequivalence (AUClast) of the lung exposure of budesonide, glycopyrronium, and formoterol administered as BGF MDI HFO compared with BGF MDI HFA was assessed.
Secondary Outcomes
- Time to Reach Peak or Maximum Observed Concentration or Response Following Drug Administration (Tmax)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Half Life Associated With Terminal Slope (λz) of a Semi Logarithmic Concentration Time Curve (t½λz)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Terminal Rate Constant (λz)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRTinf)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on Terminal Phase) (Vz/F)(Pre-dose, 2 minutes, 5 minutes,10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 h, 2 h, 4 h, 8 h, 12 h and 24 hours post-dose on Day 1 and Day 2 of each treatment period (each treatment period is of 2 days))
- Number of Participants With Adverse Events(From screening (Day -28 to Day -1) up to 55 days)