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

Zambon SpA90 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Conditions

Asthma

Interventions

Z7200 without oral activated charcoalDRUG

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).

Symbicort Turbohaler without oral activated charcoalDRUG

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).

Z7200 with oral activated charcoalDRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

Quotient Clinical Ltd

Ruddington, United Kingdom

Outcomes

Primary Outcomes

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)

AUC0-t of Formoterol With and Without Charcoal Blockade

Time frame: 0-24h (0, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, 720, and 1440 min)

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)

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)

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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