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Methacholine Challenge as a Clinical Bioassay of Pulmonary Delivery of a Long‐Acting β 2 ‐Adrenergic Agonist
Author(s) -
Prabhakaran Sreekala,
Shuster Jonathan,
Ahrens Richard,
Hendeles Leslie
Publication year - 2011
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.31.5.449
Subject(s) - medicine , methacholine , bioequivalence , dry powder inhaler , formoterol , crossover study , confidence interval , bronchodilator , asthma , anesthesia , area under the curve , dosing , agonist , inhaler , pharmacokinetics , inhalation , respiratory disease , budesonide , lung , receptor , alternative medicine , pathology , placebo
Study Objective. To determine whether the methacholine challenge method used for albuterol can be applied to assess long‐acting β 2 ‐adrenergic agonist (LABA) bioequivalence, which would require a sufficiently steep dose‐response curve. Design. Prospective, unblinded, randomized, 2–way crossover study. Setting. University medical center clinical research laboratory. Patients. 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. Intervention. 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. Measurements and Main 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 PC 20 (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). Conclusion. 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.