title: Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA).
abstract: OBJECTIVE
  The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5-3200 μg) or Turbuhaler (single delivered doses of 120-1920 μg or repeated delivered once-daily doses 240-1,680 μg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations.
  
  
  RESULTS
  AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects.
  
  
  CONCLUSIONS
  AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation.
authors.affiliation: Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.affiliation: Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kuna
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Carin
authors.initials: C
authors.lastname: Jorup
authors.affiliation: StatMind, Lund, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bengtsson
authors.affiliation: StatMind, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rosenborg
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism*; D052160:Benzothiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: C544523:AZD-3199; D058666:Adrenergic beta-2 Receptor Agonists; D052160:Benzothiazoles
keywords: AZD3199; COPD; asthma; pharmacokinetics; tolerability; uLABA