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Pharmacodynamic Determination of Inhaler Bioequivalence for Asthma and COPD

Hendeles L, Ahrens RC, Hochhaus G.

RDD Asia 2018. Volume , 2018: 37-50.

Abstract:

Generic inhalers for asthma and COPD are essential to ensure that medications are affordable for most patients. Currently, there are no US Food and Drug Administration (FDA) approved generic equivalents available, in spite of expiration of exclusivity patents. Because the dose-response effect of inhaled beta-agonist and anticholinergic bronchodilators, and inhaled corticosteroids (ICS) for forced expiratory volume in the first second (FEV1) is relatively flat, standard pulmonary function tests are not sufficiently sensitive to detect differences between a generic and brand name product. Rather, pharmacodynamic studies using other outcome measures are required to determine the relative amount of drug delivered to the airways. Studies demonstrate that bronchoprovocation with histamine or methacholine, can determine bioequivalence (BE) of generic albuterol products with less than 100 subjects and is a recommended method by FDA. In contrast, FDA recommends bronchodilator studies for long acting beta agonists (e.g., formoterol) and muscarinic antagonists (e.g. ipratropium, tiotropium), a contradiction in regulatory policy. Also, FDA recommends measurement of FEV1 for ICS which cannot truly determine BE with a sample size of 1,000 or more subjects. Measurement of exhaled nitric oxide or impulse oscillometry offers pharmacodynamic methods that might be capable of determining differences in ICS potency with around 100-200 subjects at a significant cost saving to industry.