Asthma
Conditions
Brief summary
The primary objective was: \- to assess the bioequivalence of a single dose (two inhalations) of the test product compared to the reference product, with and without charcoal blockade. The secondary objectives were: * to assess the pharmacokinetic profile of budesonide and formoterol in plasma after a single dose (two inhalations) of the test product and the reference product, with and without charcoal blockade. * to assess the safety and tolerability of the test product and the reference product, with and without charcoal blockade.
Detailed description
This was a single center, open label, randomized, five-period crossover, single-dose study in healthy volunteers aged 18 to 45 years. A total of 90 volunteers were enrolled, with 9 subjects in each of the 10 treatment sequences. The study consisted of 5 treatment periods, each lasting approximately 48h, separated by a washout period of a minimum of 5 days. RS01 and/or Symbicort Turbohaler device use training was provided on Day -1 and Day 1 of each treatment period. Subjects were screened for eligibility to participate in the study -28 to -2 days prior to the first treatment period, and were randomized to one of 10 treatment sequencies containing the following 5 treatment arms on Day 1 of the first treatment period: Treatment A: Z7200 without oral activated charcoal\* Treatment B1: Symbicort 1 without oral activated charcoal\* Treatment B2: Symbicort 2 without oral activated charcoal\* Treatment C: Z7200 with oral activated charcoal\*\* Treatment D: Symbicort with oral activated charcoal\*\* Subjects were admitted to the clinical unit at 8.00 on the morning of Day -1, and were dosed on the morning of Day 1 following an overnight fast (minimum of 8h). On Day 2, following collection of the 24-h PK blood sample, subjects were discharged. \* Subjects who received treatments A, B1 and B2 rinsed their mouth vigorously with 50 mL water for 3 to 5 sec immediately after the second inhalation. \*\* A charcoal blockade was used to prevent absorption from oropharyngeal and GI tract, in order to assess the pulmonary deposition of budesonide and formoterol, with periods performed without a charcoal blockade allowing the assessment of the total systemic exposure to the drug.
Interventions
160 ug budesonide and 4.5 ug formoterol fumarate dihydrate, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
320 ug budesonide and 9 ug formoterol fumarate dihydrate, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
160 ug budesonide and 4.5 ug formoterol fumarate dihydrate, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
320 ug budesonide and 9 ug formoterol fumarate dihydrate, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation from a Symbicort Turbohaler, with charcoal blockade (Treatment D).
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Main Inclusion Criteria: * Male or female 18 to 45 years of age. * If female, is currently not pregnant/breast feeding/ or attempting to become pregnant has a negative serum pregnancy test, or is of non-childbearing potential or is of child-bearing potential, willing to commit to using a consistent and acceptable method of birth control or is of child-bearing potential and not sexually active * Body mass index (BMI) of 18.5 to 29.9 kg/m² inclusive and a body weight ≥50 kg. Main
Exclusion criteria
* FEV1 value less than 80% of the predicted value and FEV1/FVC ratio \<0.7. * History or current evidence of a clinically significant disease or disorder capable of altering the absorption, metabolism, distribution or elimination of drugs. * History or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, haematological, neuropsychological, endocrine, gastrointestinal or pulmonary. * Presence of glaucoma, cataracts, ocular herpes simplex, malignancy, regardless of the clinical significance or current stability of the disease. * History or presence of silent infections, including positive tests for HIV1, HIV2, Hepatitis B and Hepatitis C. * Bacterial or viral infection of the upper respiratory tract (including the common cold and flu), sinus, or middle ear within 2 weeks of dosing. * Lower respiratory tract infection/pneumonia within the past 3 months. * Presence of any disease or condition or regular concomitant treatment (including vitamins and herbal products) known to interfere with the absorption, distribution, metabolism or excretion of drugs. * Screening haemoglobin value of less than 1g/dL above the ULN (or 10g/L) * History of recurrent vasovagal collapses. * History of anaphylactic/anaphylactoid reactions. * History of seizures including febrile seizures excluding childhood febrile convulsions. * Unable to demonstrate proper inhalation techniques involved in using the delivery devices at screening. * Exposure to any investigational drug within 90 days of the Screening Visit. * Known or suspected hypersensitivity or idiosyncratic reaction to any steroid, any β2 agonist,or to lactose monohydrate, leucine or Tween 80. * History of allergy to milk protein. * Use of an inhaled corticosteroid within 30 days or systemic corticosteroid within 60 days of the Screening Visit. * Use of medications or herbal medicines that are strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 30 days prior to Screening Visit * Any clinically significant abnormal laboratory value or physical finding that may interfere with the interpretation of test results or cause a health risk for the subject if he/she participates in the study. * Use of caffeine containing beverages more than 600 mg of caffeine/day. * Current smokers or ex-smokers who have stopped smoking for less than 10 years. * Recent or current (suspected) drug abuse or positive result in the drugs abuse test. * Recent or current alcohol abuse (regular drinking more than 21 units per week for males and more than 14 units per week for females \[1 unit = 4 cl spirits or equivalent\]). * Predictable poor compliance, intolerance to charcoal solution, or inability to communicate well with the study centre personnel or inability to participate in all treatment periods. * The subject is not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions, has participated in a clinical research study within the previous three months or has previously been enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t of Budesonide With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| AUC0-t of Formoterol With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| Cmax of Budesonide With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Maximum plasma level of budesonide with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| Cmax of Formoterol With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Maximum plasma level of formoterol with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax for Budesonide With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| Tmax for Formoterol With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| t1/2 for Budesonide With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| AUC0-30 of Budesonide With and Without Charcoal Blockade. | 0-30 min (0, 2, 5, 10, 15, 20, and 30 min) | Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | At 75 min (1.25 hours) post-dose | FEV1 refers to the volume of air that an individual can exhale during a forced breath in 1 second. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. and Symbicort 2, together. Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But some subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174. |
| Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC) | At 75 min (1.25 hours) post-dose | FVC = Forced vital capacity. It is the full amount of air that can be exhaled with effort in a complete breath. FEV1/FVC = Tiffenau-Pinelli Index. This parameter represents the measurement of the amount of air an individual can forcefully exhale from his/her lungs. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174. |
| Change From Baseline in Peak Expiratory Flow Rate (PEFR) | At 75 min (1.25 hours) post-dose | PEFR is the highest rate at which gases can be expelled from the lungs via an open mouth. Its measurement is a simple procedure in which an individual takes a full inspiration and blows out as forcibly as possible into an instrument called a peak flow meter, which measures the maximal gas flow in an exhalation in liters per minute. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174. |
| t1/2 for Formoterol With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| AUC0-30 of Formoterol With and Without Charcoal Blockade. | 0-30 min (0, 2, 5, 10, 15, 20, and 30 min) | Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| AUC0-∞ of Budesonide With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
| AUC0-∞ of Formoterol With and Without Charcoal Blockade | 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min) | Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. |
Countries
United Kingdom
Participant flow
Recruitment details
Subjects were screened for eligibility -28 to -2 days prior to the first treatment period. On Day -1 of the first treatment period, i.d. before randomization, subjects were trained on both the RS01 and Symbicort Turbohaler devices.
Pre-assignment details
Subjects had to have an adequate inspiratory flow rate and be able to use both inhalers. Subjects who continued to meet all entry criteria on Day -1 of treatment Period 1 and with an inspiratory flow rate of ≥60 L/min and proper device use entered the treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| A-B1-B2-C-D Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| B1-C-A-D-B2 Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| C-D-B1-B2-A Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| D-B2-C-A-B1 Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| B2-A-D-B1-C Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| D-C-B2-B1-A Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| B2-D-A-C-B1 Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| A-B2-B1-D-C Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| B1-A-C-B2-D Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| C-B1-D-A-B2 Subjects were dosed on Day 1 of each treatment period with one of the following 5 treatments according to the randomization schedule using a Williams Latin Square design:
1. Treatment A: Z7200 without oral activated charcoal
2. Treatment B1: Symbicort 1 without oral activated charcoal
3. Treatment B1: Symbicort 2 without oral activated charcoal
4. Treatment C: Z7200 with oral activated charcoal
5. Treatment D: Symbicort with oral activated charcoal
A washout period ≥5 days followed treatment periods 1 to 4.
Z7200 without activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler (Treatment A).
Symbicort Turbohaler without activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation (Treatments B1 and B2).
Z7200 with activated charcoal: 160 ug budesonide and 4.5 ug formoterol, administered as two inhalations (2 x Z7200 capsules) of budesonide 80 ug/inhalation and formoterol 2.25 ug/inhalation, using an RS01 inhaler with a charcoal blockade (Treatment C).
Symbicort Turbohaler with activated charcoal: 320 ug budesonide and 9 ug formoterol, administered as two inhalations of budesonide 160 ug/inhalation and formoterol 4.5 ug/inhalation, with charcoal blockade (Treatment D). | 9 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | C-D-B1-B2-A | B1-C-A-D-B2 | D-B2-C-A-B1 | B2-A-D-B1-C | D-C-B2-B1-A | B2-D-A-C-B1 | A-B2-B1-D-C | B1-A-C-B2-D | A-B1-B2-C-D | C-B1-D-A-B2 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 90 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants |
| Age, Continuous | 28.5 years STANDARD_DEVIATION 7.4 | 27.2 years STANDARD_DEVIATION 6 | 24.7 years STANDARD_DEVIATION 6.5 | 28.1 years STANDARD_DEVIATION 7.4 | 26.3 years STANDARD_DEVIATION 7.6 | 29.8 years STANDARD_DEVIATION 8.5 | 28.0 years STANDARD_DEVIATION 7.6 | 28.3 years STANDARD_DEVIATION 5.9 | 27.8 years STANDARD_DEVIATION 8.9 | 29.0 years STANDARD_DEVIATION 7.9 | 36.2 years STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 80 Participants | 9 Participants | 9 Participants | 9 Participants | 8 Participants | 8 Participants | 7 Participants | 9 Participants | 8 Participants | 7 Participants | 6 Participants |
| Region of Enrollment United Kingdom | 90 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants | 9 participants |
| Sex: Female, Male Female | 37 Participants | 4 Participants | 5 Participants | 1 Participants | 2 Participants | 5 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 53 Participants | 5 Participants | 4 Participants | 8 Participants | 7 Participants | 4 Participants | 4 Participants | 6 Participants | 4 Participants | 6 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 0 / 90 | 0 / 88 | 0 / 86 |
| other Total, other adverse events | 16 / 84 | 20 / 90 | 6 / 88 | 15 / 86 |
| serious Total, serious adverse events | 0 / 84 | 0 / 90 | 0 / 88 | 0 / 86 |
Outcome results
Primary
AUC0-t of Budesonide With and Without Charcoal Blockade
Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-t of Budesonide With and Without Charcoal Blockade | 1870 pg*h/mL | Geometric Coefficient of Variation 20.2 |
| Treatment B | AUC0-t of Budesonide With and Without Charcoal Blockade | 1360 pg*h/mL | Geometric Coefficient of Variation 49.4 |
| Treatment C | AUC0-t of Budesonide With and Without Charcoal Blockade | 1810 pg*h/mL | Geometric Coefficient of Variation 22.3 |
| Treatment D | AUC0-t of Budesonide With and Without Charcoal Blockade | 1330 pg*h/mL | Geometric Coefficient of Variation 52.3 |
p-value: <0.00190% CI: [129.09, 149.39]Mixed Models Analysis
p-value: <0.00190% CI: [126.13, 147.04]Mixed Models Analysis
Primary
AUC0-t of Formoterol With and Without Charcoal Blockade
Area under the plasma concentration-time curve from time zero to the last detectable level calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-t of Formoterol With and Without Charcoal Blockade | 47.4 pg*h/mL | Geometric Coefficient of Variation 26 |
| Treatment B | AUC0-t of Formoterol With and Without Charcoal Blockade | 40.1 pg*h/mL | Geometric Coefficient of Variation 58.6 |
| Treatment C | AUC0-t of Formoterol With and Without Charcoal Blockade | 44.7 pg*h/mL | Geometric Coefficient of Variation 26.8 |
| Treatment D | AUC0-t of Formoterol With and Without Charcoal Blockade | 34.5 pg*h/mL | Geometric Coefficient of Variation 78.1 |
p-value: 0.00190% CI: [109.4, 131.03]Mixed Models Analysis
p-value: <0.00190% CI: [117.33, 143.2]Mixed Models Analysis
Primary
Cmax of Budesonide With and Without Charcoal Blockade
Maximum plasma level of budesonide with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Cmax of Budesonide With and Without Charcoal Blockade | 1040 pg/mL | Geometric Coefficient of Variation 67.7 |
| Treatment B | Cmax of Budesonide With and Without Charcoal Blockade | 482 pg/mL | Geometric Coefficient of Variation 63.4 |
| Treatment C | Cmax of Budesonide With and Without Charcoal Blockade | 1090 pg/mL | Geometric Coefficient of Variation 78.9 |
| Treatment D | Cmax of Budesonide With and Without Charcoal Blockade | 542 pg/mL | Geometric Coefficient of Variation 62.4 |
p-value: <0.00190% CI: [194.02, 245.24]Mixed Models Analysis
p-value: <0.00190% CI: [174.3, 231.01]Mixed Models Analysis
Primary
Cmax of Formoterol With and Without Charcoal Blockade
Maximum plasma level of formoterol with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Cmax of Formoterol With and Without Charcoal Blockade | 11.9 pg/mL | Geometric Coefficient of Variation 38.6 |
| Treatment B | Cmax of Formoterol With and Without Charcoal Blockade | 9.53 pg/mL | Geometric Coefficient of Variation 57.5 |
| Treatment C | Cmax of Formoterol With and Without Charcoal Blockade | 12.4 pg/mL | Geometric Coefficient of Variation 35.5 |
| Treatment D | Cmax of Formoterol With and Without Charcoal Blockade | 10.6 pg/mL | Geometric Coefficient of Variation 58.4 |
p-value: <0.00190% CI: [115.93, 137.32]Mixed Models Analysis
p-value: 0.00490% CI: [107.05, 128.05]Mixed Models Analysis
Secondary
AUC0-30 of Budesonide With and Without Charcoal Blockade.
Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-30 min (0, 2, 5, 10, 15, 20, and 30 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-30 of Budesonide With and Without Charcoal Blockade. | 324 pg*h/mL | Geometric Coefficient of Variation 36.5 |
| Treatment B | AUC0-30 of Budesonide With and Without Charcoal Blockade. | 174 pg*h/mL | Geometric Coefficient of Variation 62 |
| Treatment C | AUC0-30 of Budesonide With and Without Charcoal Blockade. | 342 pg*h/mL | Geometric Coefficient of Variation 38.3 |
| Treatment D | AUC0-30 of Budesonide With and Without Charcoal Blockade. | 193 pg*h/mL | Geometric Coefficient of Variation 63.4 |
Secondary
AUC0-30 of Formoterol With and Without Charcoal Blockade.
Area under the plasma concentration-time curve from time zero to 30 minutes calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-30 min (0, 2, 5, 10, 15, 20, and 30 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-30 of Formoterol With and Without Charcoal Blockade. | 3.85 pg*h/mL | Geometric Coefficient of Variation 33 |
| Treatment B | AUC0-30 of Formoterol With and Without Charcoal Blockade. | 3.12 pg*h/mL | Geometric Coefficient of Variation 54.4 |
| Treatment C | AUC0-30 of Formoterol With and Without Charcoal Blockade. | 4.00 pg*h/mL | Geometric Coefficient of Variation 32.1 |
| Treatment D | AUC0-30 of Formoterol With and Without Charcoal Blockade. | 3.35 pg*h/mL | Geometric Coefficient of Variation 58.2 |
Secondary
AUC0-∞ of Budesonide With and Without Charcoal Blockade
Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-∞ of Budesonide With and Without Charcoal Blockade | 1980 pg*h/mL | Geometric Coefficient of Variation 20.5 |
| Treatment B | AUC0-∞ of Budesonide With and Without Charcoal Blockade | 1450 pg*h/mL | Geometric Coefficient of Variation 48.8 |
| Treatment C | AUC0-∞ of Budesonide With and Without Charcoal Blockade | 1900 pg*h/mL | Geometric Coefficient of Variation 22.4 |
| Treatment D | AUC0-∞ of Budesonide With and Without Charcoal Blockade | 1410 pg*h/mL | Geometric Coefficient of Variation 50.1 |
Secondary
AUC0-∞ of Formoterol With and Without Charcoal Blockade
Area under the plasma concentration-time curve from time zero to infinity calculations were performed using the linear trapezoidal rule. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | AUC0-∞ of Formoterol With and Without Charcoal Blockade | 56.0 pg*h/mL | Geometric Coefficient of Variation 28.2 |
| Treatment B | AUC0-∞ of Formoterol With and Without Charcoal Blockade | 49.8 pg*h/mL | Geometric Coefficient of Variation 57.1 |
| Treatment C | AUC0-∞ of Formoterol With and Without Charcoal Blockade | 54.5 pg*h/mL | Geometric Coefficient of Variation 27.7 |
| Treatment D | AUC0-∞ of Formoterol With and Without Charcoal Blockade | 45.2 pg*h/mL | Geometric Coefficient of Variation 61.6 |
Secondary
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
FEV1 refers to the volume of air that an individual can exhale during a forced breath in 1 second. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. and Symbicort 2, together. Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But some subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.
Time frame: At 75 min (1.25 hours) post-dose
Population: Safety population: all subjects who received at least one dose (2 inhalations) of investigational medicinal product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 0.2 liters | Standard Deviation 0.2 |
| Treatment B | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 0.2 liters | Standard Deviation 0.2 |
| Treatment C | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 0.2 liters | Standard Deviation 0.2 |
| Treatment D | Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) | 0.2 liters | Standard Deviation 0.2 |
Secondary
Change From Baseline in Peak Expiratory Flow Rate (PEFR)
PEFR is the highest rate at which gases can be expelled from the lungs via an open mouth. Its measurement is a simple procedure in which an individual takes a full inspiration and blows out as forcibly as possible into an instrument called a peak flow meter, which measures the maximal gas flow in an exhalation in liters per minute. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.
Time frame: At 75 min (1.25 hours) post-dose
Population: Safety population: all subjects who received at least one dose (2 inhalations) of investigational medicinal product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Change From Baseline in Peak Expiratory Flow Rate (PEFR) | 22.2 L/min | Standard Deviation 48.9 |
| Treatment B | Change From Baseline in Peak Expiratory Flow Rate (PEFR) | 20.5 L/min | Standard Deviation 38.7 |
| Treatment C | Change From Baseline in Peak Expiratory Flow Rate (PEFR) | 24.8 L/min | Standard Deviation 35.5 |
| Treatment D | Change From Baseline in Peak Expiratory Flow Rate (PEFR) | 19.2 L/min | Standard Deviation 38.9 |
Secondary
Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC)
FVC = Forced vital capacity. It is the full amount of air that can be exhaled with effort in a complete breath. FEV1/FVC = Tiffenau-Pinelli Index. This parameter represents the measurement of the amount of air an individual can forcefully exhale from his/her lungs. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together. Please note that, within the safety population, 90 subjects received Treatment B. This would mean that theorically 180 participants received Symbicort 1 and Symbicort 2, together. But 6 subjects were excluded from the statistical analysis for various reasons so that the total number included in the statistical anlysis for treatment B is 174.
Time frame: At 75 min (1.25 hours) post-dose
Population: Safety population: all subjects who received at least one dose (2 inhalations) of investigational medicinal product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC) | 3.7 ratio | Standard Deviation 3 |
| Treatment B | Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC) | 3.6 ratio | Standard Deviation 3.4 |
| Treatment C | Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC) | 3.2 ratio | Standard Deviation 3.1 |
| Treatment D | Change From Baseline in the Ratio of Forced Expiratory Volume in 1 Second to Forced Vital Capacity (FEV1/FVC) | 3.8 ratio | Standard Deviation 3.2 |
Secondary
t1/2 for Budesonide With and Without Charcoal Blockade
Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | t1/2 for Budesonide With and Without Charcoal Blockade | 2.90 hours | Geometric Coefficient of Variation 17 |
| Treatment B | t1/2 for Budesonide With and Without Charcoal Blockade | 2.94 hours | Geometric Coefficient of Variation 19.8 |
| Treatment C | t1/2 for Budesonide With and Without Charcoal Blockade | 2.79 hours | Geometric Coefficient of Variation 17 |
| Treatment D | t1/2 for Budesonide With and Without Charcoal Blockade | 2.80 hours | Geometric Coefficient of Variation 15.8 |
Secondary
t1/2 for Formoterol With and Without Charcoal Blockade
Apparent elimination half-life calculated as 0.693/lambda zeta, with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A | t1/2 for Formoterol With and Without Charcoal Blockade | 9.57 hours | Geometric Coefficient of Variation 29.3 |
| Treatment B | t1/2 for Formoterol With and Without Charcoal Blockade | 9.33 hours | Geometric Coefficient of Variation 35.2 |
| Treatment C | t1/2 for Formoterol With and Without Charcoal Blockade | 10.09 hours | Geometric Coefficient of Variation 29.8 |
| Treatment D | t1/2 for Formoterol With and Without Charcoal Blockade | 9.15 hours | Geometric Coefficient of Variation 33.6 |
Secondary
Tmax for Budesonide With and Without Charcoal Blockade
Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Tmax for Budesonide With and Without Charcoal Blockade | 0.08 hours |
| Treatment B | Tmax for Budesonide With and Without Charcoal Blockade | 0.25 hours |
| Treatment C | Tmax for Budesonide With and Without Charcoal Blockade | 0.08 hours |
| Treatment D | Tmax for Budesonide With and Without Charcoal Blockade | 0.25 hours |
Secondary
Tmax for Formoterol With and Without Charcoal Blockade
Time at which the maximum plasma level (Cmax) occurred with and without charcoal blockade. Participants for the Treatment B are counted for both Symbicort 1 and Symbicort 2, together.
Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)
Population: PK population included subjects who had received both test and reference for at least one dose of each treatment without or with oral charcoal.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Tmax for Formoterol With and Without Charcoal Blockade | 0.08 hours |
| Treatment B | Tmax for Formoterol With and Without Charcoal Blockade | 0.08 hours |
| Treatment C | Tmax for Formoterol With and Without Charcoal Blockade | 0.08 hours |
| Treatment D | Tmax for Formoterol With and Without Charcoal Blockade | 0.08 hours |