A Clinical Study to Evaluate Z7200 (Budesonide/Formoterol) Pharmacokinetics Profile in Healthy Volunteers

An Open-Label, Single-dose, Randomized, Five-Period Cross-over to Compare Pharmacokinetics Profiles of Z7200 and Symbicort Turbohaler, With and Without Charcoal Blockade in Healthy Volunteers.

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 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.

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.