%0 Journal Article
%T Pharmacological Basis of Differences in Dose Response, Dose Equivalence, and Duration of Action of Inhaled Corticosteroids.
%A Daley-Yates PT
%A Aggarwal B
%A Plank M
%J Adv Ther
%V 41
%N 5
%D 2024 May 27
%M 38532238
%F 4.07
%R 10.1007/s12325-024-02823-y
%X <B>BACKGROUND: </B>Asthma treatment guidelines classify inhaled corticosteroid (ICS) regimens as low, medium, or high dose. However, efficacy and safety are not independently assessed accordingly. Moreover, differences in ICS duration of action are not considered when a dose regimen is selected. We investigated the efficacy and safety implications of these limitations for available ICS molecules.<BR><B>METHODS: </B>Published pharmacodynamic and pharmacokinetic parameters were used, alongside physiological and pharmacological principles, to estimate the efficacy and safety of available ICS molecules. Extent and duration of glucocorticoid receptor (GR) occupancy in the lung (efficacy) and cortisol suppression (systemic exposure and safety) were estimated.<BR><B>RESULTS: </B>Some ICS regimens (e.g., fluticasone furoate, fluticasone propionate, and ciclesonide) rank high for efficacy but low for systemic exposure, contrary to how ICS dose equivalence is currently viewed. Differences in dose-response relationships for efficacy and systemic exposure were unique for each ICS regimen and reflected in their therapeutic indices. Notably, even low doses of most ICSs can generate high GR occupancy (≥ 90%) across the entire dose interval at steady state, which may explain previously reported difficulties in obtaining dose responses within the clinical dose range and observations that most clinical benefit typically occurs at low doses. The estimated post dose duration of lung GR occupancy for ICS molecules was categorized as 4-6 h (short), 14-16 h (medium), 25-40 h (long), or > 80 h (ultra-long), suggesting potentially large differences in anti-inflammatory duration of action.<BR><B>CONCLUSIONS: </B>In a real-world clinical setting where there may be poor adherence to prescribed therapy, our findings suggest a significant therapeutic advantage for longer-acting ICS molecules in patients with asthma.<BR>Patients with asthma often rely on inhaled corticosteroids to manage their symptoms by controlling lung inflammation. Inhaled corticosteroids can be used at low, medium, or high doses; however, the effectiveness, safety, and how long the effects last for a particular inhaled corticosteroid molecule are not considered when choosing them. This study investigated the safety and efficacy of different inhaled corticosteroid molecules. Leveraging published data on the mode of anti-inflammatory action and the rates these molecules are absorbed and eliminated from the body, we estimated their effectiveness and safety profiles, including duration of action in the lungs and systemic exposure levels. Some inhaled corticosteroid molecules such as fluticasone furoate, fluticasone propionate, and ciclesonide were found to exhibit high anti-inflammatory effectiveness in the lungs with minimal systemic exposure, contrasting the perceived similarities among currently used drug molecules. Anti-inflammatory duration of the unwanted systemic effect in the rest of the body was unique for each inhaled corticosteroid molecule. Notably, even the lowest doses of most inhaled corticosteroids were found to be effective in the lungs when taken as prescribed, supporting previous observations that clinical benefits are mostly realized at lower doses. Furthermore, estimated post dose durations of effectiveness for different inhaled corticosteroid molecules varied widely among different molecules, with some lasting a few hours and others lasting more than 80 h, suggesting significant differences in their duration of action. Overall, these findings demonstrate the potential advantage of using longer-acting inhaled corticosteroids, particularly for patients with asthma who may face challenges in adhering to prescribed regimens.