Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma

Abstract

The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma.Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the antiinflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance.The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamicpituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning.Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.

Erratum to: Safety Considerations of Inhaled Corticosteroids in the Elderly

“…Both these actions have as a result an altered transcription of pro-and anti-inflammatory genes. The main pharmacokinetic/dynamic properties [9][10][11] depend on (a) receptor affinity [12]; (b) particle size and formulation [13,14]; (c) oral, pulmonary, and systemic bioavailability [15][16][17][18]; (d) half-life [17]; (e) protein binding [19]; (f) bioactivation [17,20]; (g) lipophilicity; (h) lipid conjugation [8]; and (i) metabolism [17].…”

“…ICS in systemic circulation mainly originates from the amount deposited in the oropharynx, which is swallowed, and then adsorbed through the gastrointestinal tract. Moreover, a small fraction of the drug deposited in the lung can be adsorbed through the pulmonary vasculature [10]. The systemic effects are related to the hypothalamic-pituitary-adrenal (HPA) axis suppression and depend on dose, duration of treatment, and timing of corticosteroid administration [9,10].…”

Fluticasone propionate/formoterol: A fixed-combination therapy with flexible dosage

“…Fluticasone propionate is one of the most potent ICSs [35]. It has a very low oral bioavailability (≤ 1%) [35] and it is well accepted that low oral availability (b 10%) decreases systemic availability and the incidence of adverse events [38]. High receptor binding strength is correlated with high anti-inflammatory activity [39].…”

“…Moreover, fluticasone propionate is the most lipophilically active ICS [35], and therefore has a long duration of anti-inflammatory action. In fact, higher lipophilicity is positively correlated with increased retention in the lung and longer duration of action [38]. Table 1 Expert panel agreement ⁎ on the characteristics of an effective ICS/LABA combination therapy.…”

“…Pharmacological characteristics that could theoretically optimize ICS effectiveness include a low oral and a high pulmonary bioavailability, high receptor-binding affinity, high protein-binding capacity and a long pulmonary retention time [38]. Important properties for a LABA include speed of onset of action, duration of action and agonist activity at the β 2 -adrenoceptor [41].…”