a clinical study to evaluate z7200 (budesonide/formoterol) pharmacokinetics profile in healthy volunteers

Conditions: Asthma

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 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.

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 18.5 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.