Inhaled corticosteroids: potency, dose equivalence and therapeutic index

Abstract

Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles.

Integrated safety and efficacy analysis of once-daily fluticasone furoate for the treatment of asthma

“…Consistent with previous results [37], the data presented here suggest that FF has a wide therapeutic index; the therapeutic dose range was efficacious across individual studies, with a tolerability profile as expected for the class and no evidence of cortisol suppression at the doses assessed.…”

Triamcinolone Acetonide versus Fluticasone Propionate in the Treatment of Perennial Allergic Rhinitis: A Randomized, Parallel-Group Trial

“…The clinical equivalence of single daily doses of 220 µg of triamcinolone acetonide and 200 µg of fluticasone propionate that was documented in this study and in prior studies shows that the higher molecular potency of fluticasone propionate compared to triamcinolone acetonide does not translate into superior clinical efficacy [24, 25]. This lack of clinical differentiation may be explained by the inhibition of the inflammatory processes in AR by recommended doses of glucocorticoids of various potencies that may far exceed the minimally effective doses [24].…”

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

“…Upon ligand binding, GR as a homodimer translocates to the nucleus and binds to GC response elements on DNA, further promoting activation of gene transcription (36). Structural modifications in different synthetic GC molecules significantly modulate their affinity for GR (37), which influences their potency for transcription of target genes. A recent pharmacodynamic investigation of GR-mediated gene transactivation in the HBEC line BEAS-2B revealed a lower maximum response of a transfected reporter construct to cortisol (hydrocortisone) compared with several other synthetic GCs (31), raising the question of whether endogenous cortisol could antagonize synthetic anti-inflammatory GCs.…”