Methacholine Challenge as a Clinical Bioassay of Pulmonary Delivery of a Long-Acting β2-Adrenergic Agonist

  • Prabhakaran, Sreekala M.D.
  • Shuster, Jonathan Ph.D.
  • Ahrens, Richard M.D.
  • Hendeles, Leslie Pharm.D.

From the Pediatric Pulmonary Division (Drs. Prabhakaran and Hendeles) and the Division of Biostatistics, Department of Epidemiology-Health Policy Research (Dr. Shuster), College of Medicine, and the Department of Pharmacotherapy and Translational Research, College of Pharmacy (Dr. Hendeles), University of Florida, Gainesville, Florida; and the Allergy/Pulmonary Division, Department of Pediatrics, University of Iowa, Iowa City, Iowa (Dr. Ahrens).

Supported by an investigator-initiated grant from Teva/IVAX Pharmaceuticals, and from the U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Bureau, Pediatric Pulmonary Center fellowship training grant (T72MC000002), and National Institutes of Health (NIH) Research Facilities Construction Program C06 (grant RR17568). Dr. Shuster is supported by NIH General Clinical Research Center grants (M01RR00082 and U54RR025208).

Manuscript received October 6, 2010. Accepted pending revisions November 11, 2010. Accepted for publication in final form December 2, 2010.

For reprints, visit http://www.atypon-link.com/PPI/loi/phco. For questions or comments, contact Leslie Hendeles, Pharm.D., the Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0486; e-mail: [email protected].

Pharmacotherapy: The Journal Of Human Pharmacology & Drug Therapy 31(5):p 449-457, May 2011.

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 [FEV1] ≥ 70% predicted) and a baseline provocational concentration of methacholine required to decrease FEV1 by 20% (PC20) 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 FEV1 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 FEV1 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).

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.

Copyright © 2011 John Wiley & Sons, Inc.