title: Methacholine challenge as a clinical bioassay of pulmonary delivery of a long-acting β₂-adrenergic agonist.
abstract: OBJECTIVE
  To determine whether the methacholine challenge method used for albuterol can be applied to assess long-acting β2-adrenergic agonist (LABA) bioequivalence, which would require a sufficiently steep dose-response curve.
  
  
  METHODS
  Prospective, unblinded, randomized, 2-way crossover study.
  
  
  METHODS
  University medical center clinical research laboratory.
  
  
  METHODS
  Ten adults, aged 21-58 years, with mild asthma (forced expiratory volume in 1 sec [FEV(1)] ≥ 70% predicted) and a baseline provocational concentration of methacholine required to decrease FEV(1) by 20% (PC(20)) of 4 mg/ml or less completed the study.
  
  
  METHODS
  Patients were randomized to receive a single dose of either 12 or 24 μg of formoterol delivered by a dry powder inhaler; 3-7 days later, at the same time of day, they received the other dose.
  
  
  RESULTS
  The FEV(1) was measured before and 1 hour after dosing, followed by performance of a methacholine challenge. Statistical analysis was performed by the 2-sample regression method for crossover studies. The dose-response curve for bronchodilatation was flat; the mean ± SD increase in FEV(1) after formoterol 12 and 24 μg was 14 ± 5% and 14 ± 8%, respectively (p>0.05). In contrast, the geometric mean PC20 (95% confidence interval) was 7 mg/ml (2-22 mg/ml) after the 12-μg dose and 16 mg/ml (5-45 mg/ml) after the 24-μg dose (p<0.001).
  
  
  CONCLUSIONS
  Bioassay by methacholine challenge will be useful for bioequivalence studies of LABAs. A sample of at least 28 patients will be required for formoterol when methacholine challenge is performed in an optimal manner. The sample size may differ for other LABAs.
authors.affiliation: Pediatric Pulmonary Division, University of Florida, Gainesville, Florida 32610-0486, USA.
authors.forename: Sreekala
authors.initials: S
authors.lastname: Prabhakaran
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shuster
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Leslie
authors.initials: L
authors.lastname: Hendeles
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D006785:Hospitals, University; D006801:Humans; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D012720:Severity of Illness Index; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D016210:Methacholine Chloride; D000068759:Formoterol Fumarate