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.

Keywords: Corticosteroid; dose equivalence; inhaled; potency; therapeutic index.

Figure 1

Chemical structures of synthetic glucocorticoids

Figure 2

Relationship between glucocorticoid receptor binding affinity (Table 1) and mid-range nominal therapeutic daily doses [53] of inhaled corticosteroids (ICS) (r² = 0.980)

Figure 3

Relationship between glucocorticoid receptor binding affinity (Table 1) and estimated daily lung dose [53, 54] (Table 1) for therapeutic doses in low- (♦) (r² = 0.825), mid- (▲) (r² = 0.934) and high- (▪) dose ranges (r² = 0.947) of inhaled corticosteroids (ICS). This analysis includes ICS dose regimens that are not approved for clinical use

Figure 4

Relationship between glucocorticoid receptor binding affinity (Table 1) and the corresponding inhaled corticosteroid glucocorticoid receptor dissociation constant (Kd, nmol l^–1), which is the concentration needed to occupy 50% of glucocorticoid receptors

Figure 5

Relationship between glucocorticoid receptor binding affinity (Table 1) and the therapeutic index for various inhaled corticosteroid dose regimens. Therapeutic index is defined as the daily dose that produces 20% cortisol suppression divided by either the low–mid (♦) or mid–high (▲) therapeutic daily dose [23,53,54]