PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
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.
摘要：
背景：哮喘治疗指南将吸入性皮质类固醇（ICS）方案分类为低，中等,或高剂量。然而,疗效和安全性没有独立评估。此外，在选择给药方案时,不考虑ICS作用持续时间的差异.我们研究了这些限制对可用ICS分子的功效和安全性影响。
方法：使用已发布的药效学和药代动力学参数，除了生理学和药理学原理，评估可用ICS分子的疗效和安全性。估计了肺中糖皮质激素受体（GR）占据的程度和持续时间（功效）和皮质醇抑制（全身暴露和安全性）。
结果：一些ICS方案(例如，糠酸氟替卡松,丙酸氟替卡松,和环索奈德）的疗效较高，但对于全身暴露，与目前如何看待ICS剂量等效相反。疗效和全身暴露的剂量-反应关系的差异对于每个ICS方案是独特的，并反映在它们的治疗指数中。值得注意的是,即使低剂量的大多数ICSs可以在稳定状态的整个剂量间隔内产生高GR占有率（≥90％），这可能解释了先前报道的在临床剂量范围内获得剂量反应的困难，以及观察到大多数临床益处通常发生在低剂量。ICS分子的肺GR占用的估计剂量后持续时间被分类为4-6小时(短)，14-16小时（中等），25-40小时（长），或>80小时（超长），提示抗炎作用持续时间可能存在较大差异。
结论：在现实世界的临床环境中，对处方治疗的依从性可能较差，我们的研究结果表明,在哮喘患者中,长效ICS分子具有显著的治疗优势.
哮喘患者通常依赖吸入糖皮质激素通过控制肺部炎症来控制症状。吸入皮质类固醇可以在低，中等,或高剂量；然而，的有效性,安全,选择时，不考虑特定吸入皮质类固醇分子的作用持续多长时间。这项研究调查了不同吸入皮质类固醇分子的安全性和有效性。利用已发表的关于抗炎作用模式的数据，以及这些分子从体内吸收和消除的速率，我们估计了它们的有效性和安全性,包括在肺部的作用持续时间和全身暴露水平。一些吸入的皮质类固醇分子，例如糠酸氟替卡松，丙酸氟替卡松,和环索奈德被发现在肺部表现出高度的抗炎效果与最小的全身暴露，对比目前使用的药物分子之间的感知相似性。对于每个吸入的皮质类固醇分子，身体其余部分中不需要的全身作用的抗炎持续时间是独特的。值得注意的是,即使是最低剂量的大多数吸入性皮质类固醇被发现在肺部有效时，支持先前的观察，即临床获益大多在较低剂量下实现。此外，不同吸入性皮质类固醇分子的估计剂量后有效性持续时间在不同分子之间差异很大，有些持续几个小时，有些持续超过80小时，表明他们的作用时间存在显著差异。总的来说,这些发现证明了使用长效吸入性糖皮质激素的潜在优势，特别是对于在坚持处方治疗方案方面可能面临挑战的哮喘患者。
方法：使用已发布的药效学和药代动力学参数，除了生理学和药理学原理，评估可用ICS分子的疗效和安全性。估计了肺中糖皮质激素受体（GR）占据的程度和持续时间（功效）和皮质醇抑制（全身暴露和安全性）。
结果：一些ICS方案(例如，糠酸氟替卡松,丙酸氟替卡松,和环索奈德）的疗效较高，但对于全身暴露，与目前如何看待ICS剂量等效相反。疗效和全身暴露的剂量-反应关系的差异对于每个ICS方案是独特的，并反映在它们的治疗指数中。值得注意的是,即使低剂量的大多数ICSs可以在稳定状态的整个剂量间隔内产生高GR占有率（≥90％），这可能解释了先前报道的在临床剂量范围内获得剂量反应的困难，以及观察到大多数临床益处通常发生在低剂量。ICS分子的肺GR占用的估计剂量后持续时间被分类为4-6小时(短)，14-16小时（中等），25-40小时（长），或>80小时（超长），提示抗炎作用持续时间可能存在较大差异。
结论：在现实世界的临床环境中，对处方治疗的依从性可能较差，我们的研究结果表明,在哮喘患者中,长效ICS分子具有显著的治疗优势.
哮喘患者通常依赖吸入糖皮质激素通过控制肺部炎症来控制症状。吸入皮质类固醇可以在低，中等,或高剂量；然而，的有效性,安全,选择时，不考虑特定吸入皮质类固醇分子的作用持续多长时间。这项研究调查了不同吸入皮质类固醇分子的安全性和有效性。利用已发表的关于抗炎作用模式的数据，以及这些分子从体内吸收和消除的速率，我们估计了它们的有效性和安全性,包括在肺部的作用持续时间和全身暴露水平。一些吸入的皮质类固醇分子，例如糠酸氟替卡松，丙酸氟替卡松,和环索奈德被发现在肺部表现出高度的抗炎效果与最小的全身暴露，对比目前使用的药物分子之间的感知相似性。对于每个吸入的皮质类固醇分子，身体其余部分中不需要的全身作用的抗炎持续时间是独特的。值得注意的是,即使是最低剂量的大多数吸入性皮质类固醇被发现在肺部有效时，支持先前的观察，即临床获益大多在较低剂量下实现。此外，不同吸入性皮质类固醇分子的估计剂量后有效性持续时间在不同分子之间差异很大，有些持续几个小时，有些持续超过80小时，表明他们的作用时间存在显著差异。总的来说,这些发现证明了使用长效吸入性糖皮质激素的潜在优势，特别是对于在坚持处方治疗方案方面可能面临挑战的哮喘患者。
