Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles
Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles
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DOI：
10.1210/jc.2008-2380
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Ross, Richard J.
中科院分区：
文献类型：
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作者：
Debono, Miguel;Ghobadi, Cyrus;Ross, Richard J.
背景：皮质醇有一个独特的昼夜节律，由大脑的中央起搏器调节。这种节律的丧失与代谢异常、疲劳和生活质量差有关。传统的糖皮质激素替代不能复制这种节律。目的：我们的目的是定义生理皮质醇节律的关键变量，并通过药代动力学建模测试，改良释放氢化可的松（MR-HC）是否可以提供昼夜皮质醇曲线。设置：该研究在临床研究机构进行。设计和方法：使用健康参考受试者（n = 33）的横断面研究数据，我们定义了皮质醇节律的参数。然后，我们在一项开放标签、随机、单次给药、交叉研究中，在健康志愿者（n = 28）中测试了MR-HC与速释氢化可的松的对比。我们比较了生理皮质醇水平的配置文件，并模拟了最佳的治疗方案。结果：生理皮质醇配置文件中的关键变量包括：峰值15.5 μ g/dl（95%参考范围11.7-20.6），峰值相0832 h（95%置信区间0759-0905），最低值小于2 μ g/dl（95%参考范围1.5-2.5），最低点时间0018 h（95%置信区间2339-0058），静止期（低于中位）1943-0531 h。MR-HC 15 mg表现出延迟释放和持续释放，给药后7.41（0.57）h时观察到的平均（SEM）最大浓度为16.6（1.4）μ g/dl。MR-HC 5、10和15 mg的生物利用度分别为速释氢化可的松的100、79和86%。建模表明，MR-HC 15-20毫克在2300小时和10毫克在0700小时可以重现生理cortisol levels.Conclusion：通过定义昼夜节律和使用现代制剂技术，它是可能的，以允许一个更生理的昼夜替代皮质醇。（临床内分泌代谢杂志94：1548-1554，2009）
Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.Setting: The study was performed at a Clinical Research Facility.Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009)