Methacholine Challenge as a Clinical Bioassay of Pulmonary Delivery of a Long-Acting β2-Adrenergic Agonist.
Abstract Study 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. 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 £g 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 £g 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-£g dose and 16 mg/ml (5-45 mg/ml) after the 24-£g 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.[1]References
- Methacholine Challenge as a Clinical Bioassay of Pulmonary Delivery of a Long-Acting β2-Adrenergic Agonist. Prabhakaran, S., Shuster, J., Ahrens, R., Hendeles, L. Pharmacotherapy (2011) [Pubmed]
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