Clinical Study to Evaluate Z7200 Pharmacokinetics Profile

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.

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 planned to be 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 sequences 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.

Eligibility 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 18.0 to 32.0 kg/m² inclusive and a body weight ≥50 kg.
* 10 years or more past history of cigarette, \<=5 pack year

Main Exclusion Criteria:

* Forced Expiratory Volume in 1 sec (FEV1) value less than 80% of the predicted value and FEV1/FVC (Forced Vital Capacity) 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.
* positive tests for Human Immunodeficiency Virus (HIV), 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 Lower Limit of Normality
* 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; 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 5 cups/day.
* 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)
* 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.