Measuring safety of inhaled corticosteroids in asthma

Abstract

Background: Despite evidence demonstrating generally excellent therapeutic ratios for inhaled corticosteroids (ICSs) in asthma treatment, many clinicians and patients have ongoing concerns regarding their safety. To frame discussions of ICS safety, it is important to understand how safety is measured.

Objective: To discuss how ICS safety is and should be measured.

Methods: Discussion is augmented by relevant articles from the literature.

Results: The therapeutic value of corticosteroids depends on the activation and repression of thousands of genes. However, it is not fully known which genes cause the desirable, therapeutic effects and which cause the adverse effects. The drug development process attempts to elucidate the clinically significant therapeutic effects and adverse effects of a candidate molecule and then compare them to those of currently available corticosteroids. Approaches to monitoring safety include clinical trials, retrospective comparison to historical efficacy and safety data, surrogate markers, animal models, and in vitro assays. Both preclinical and clinical data are used to compare safety among corticosteroids; however, no specific pathway or model that can robustly predict therapeutic ratios has been identified. Furthermore, variation in adverse effects is influenced by isoforms of the glucocorticoid receptor, differences in corticosteroid characteristics, differences among patients, and environmental variation.

Conclusion: Although some preclinical and patient-based metrics have predictive value, there is a clear need for improved biomarkers of corticosteroid adverse effects. Integrated analysis of preclinical and clinical data, including long-term safety data, could be used to address this important unmet need.