Relationship between systemic corticosteroid exposure and growth velocity: Development and validation of a pharmacokinetic/pharmacodynamic model
Relationship between systemic corticosteroid exposure and growth velocity: Development and validation of a pharmacokinetic/pharmacodynamic model
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DOI：
10.1016/j.clinthera.2004.11.017
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发表时间：
2004-11-01
影响因子：
3.2
通讯作者：
Richards, DH
中科院分区：
文献类型：
--
作者：
Daley-Yates, PT;Richards, DH
背景：使用大剂量口服皮质类固醇(CS)可以减慢儿童的生长速度(GV)，而使用小剂量局部皮质类固醇对短期生长没有影响或短暂影响，对最终成人身高没有影响。尽管关于这一主题的文献很多，但关于CS暴露与生长效应之间的关系仍然存在一些基本问题。目的：本研究的目的是确定接受CS治疗的哮喘或鼻炎儿童中CS暴露与GV的关系，以及GV与皮质醇抑制之间是否可能存在联系。方法：通过基于生理学的药代动力学/药效学方法，通过在皮质醇等效物中表达CS暴露，巩固了32项已发表的研究数据，这些研究涉及吸入、鼻腔和口服CS对生长的影响。用非线性S型最大效应(E-max)模型描述了皮质醇当量中GV和CS暴露之间的关系，模型参数如下：E-max=-5.9 cm/y；皮质醇当量GV减少50%的稳态非结合AUC=20,000 ng/h/L，Hill常数=1.2；以及零全身暴露时GV的变化=0.06 cm/y。通过将模型的预测与5项研究的数据进行比较，验证了该模型的有效性。该模型还被用来预测不同CS方案降低GV的潜力。结果：探索性数据分析证实GV的变化与皮质醇等效物的暴露高度相关(P<；0.001)。通过鼻腔途径具有高系统生物利用度的CS被预测具有超过GV变化的临床等效限(+/-0.8 cm/y)的短期生长效应，而那些生物利用度较低的CS被预测产生低于GV显著影响的全身性暴露的阈值。对于吸入的CS和通过鼻腔和吸入途径联合给药的方案，结果是相似的。按降序，该模型预测了以下各种鼻内、吸入和口服方案降低GV的潜力排名，以儿童剂量的分数或倍数表示(以杯/天为单位)：口服泼尼松龙5000杯/天，0.14；吸入二丙酸倍氯米松计量吸入器400杯/天，0.54；布地奈德干粉吸入器400杯/天，0.66；曲安奈德鼻腔喷雾剂220杯/天，0.74；吸入曲安奈德计量吸入器400克/天，0.75；吸入二丙酸倍氯米松水雾剂336克/天，0.89吸入呋喃莫米松干粉吸入剂200杯/天，2.4次；布地奈德鼻腔喷雾剂128杯/天，2.5次；丙酸氟替卡松干粉吸入器200杯/天，2.6次；呋喃酸莫米松鼻腔喷雾剂100杯/天，120次；丙酸氟替卡松鼻腔喷雾剂100杯/天，150次。>；1值对GV没有显著影响。该模型预测，在生长减少的下限(-0.8 cm/年)，血浆皮质醇浓度下降10%到15%应该是可以检测到的。验证过程表明，该模型能够预测模型开发中未包括的5项比较生长研究的结果，相关系数为0.98。结论：生长效应与CS暴露似乎是非线性相关的，因此，对于全身暴露较低的CS，应该可以选择无影响暴露。在皮质醇浓度没有明显下降的情况下，生长抑制似乎不太可能发生。版权所有(C)2004 Excerpta Medica，Inc.
Background: Use of high-dose oral corticosteroids (CSs) can reduce growth velocity (GV) in children, whereas use of low-dose topical CSs has either no effect or transient effects on short-term growth and no effect on final adult height. Despite the large body of literature on this topic, some fundamental questions remain concerning the relationship between CS exposure and growth effects.Objectives: The aims of this study were to determine the relationship between CS exposure and GV in children receiving CS therapy for asthma or rhinitis, and to examine whether there is likely to be a link between GV and cortisol suppression.Methods: Data from 32 published studies of the effect on growth of inhaled, intranasal, and oral CSs, including delivery by dry powder inhaler, metered-dose inhaler, and aqueous nasal spray, were consolidated by expressing CS exposure in cortisol equivalents using a physiologically based pharmacokinetic/pharmacodynamic approach. The relationship between change in GV and CS exposure in cortisol equivalents was described using a nonlinear sigmoid maximum-effect (E-max) model with the following parameters: E-max = -5.9 cm/y; steady-state unbound AUC for 50% reduction in GV in cortisol equivalents = 20,000 ng(.)h/L, Hill constant = 1.2; and change in GV at zero systemic exposure = 0.06 cm/y. Validation was achieved by comparing the model's predictions with data from 5 studies that were not included in the model development. The model was also used to predict the potential of various CS regimens to reduce GV.Results: Exploratory data analysis established that change in GV was highly correlated with exposure in cortisol equivalents (P < 0.001). CSs with high systemic bioavailability by the intranasal route were predicted to have short-term growth effects exceeding the clinical equivalence limit for change in GV (+/-0.8 cm/y), whereas those with lower bioavailability were predicted to produce systemic exposures below the threshold for significant effects on GV. The findings were similar for inhaled CSs and for regimens combining delivery by the intranasal and inhaled routes. In descending order, the model predicted the following ranking of the potential of the various intranasal, inhaled, and oral regimens to reduce GV, expressed as fractions or multiples of the pediatric dose (in mug/d): oral prednisolone 5000 mug/d, 0.14; inhaled beclomethasone dipropionate metered-dose inhaler 400 mug/d, 0.54; inhaled budesonide dry powder inhaler 400 mug/d, 0.66; intranasal triamcinolone acetonide aqueous nasal spray 220 mug/d, 0.74; inhaled triamcinolone acetonide metered-dose inhaler 400 mug/d, 0.75; intranasal beclomethasone dipropionate aqueous nasal spray 336 mug/d, 0.89; inhaled mometasone furoate dry powder inhaler 200 mug/d, 2.4; intranasal budesonide aqueous nasal spray 128 mug/d, 2.5; inhaled fluticasone propionate dry powder inhaler 200 mug/d, 2.6; intranasal mometasone furoate aqueous nasal spray 100 mug/d, 120; and intranasal fluticasone propionate aqueous nasal spray 100 mug/d, 150. Values >1 are predictive of no significant effect on GV The model predicted that a 10% to 15% reduction in plasma cortisol concentration should be detectable at the lower equivalence limit for growth reduction (-0.8 cm/y). The validation procedure showed that the model was capable of predicting the results of the 5 comparative growth studies not included in model development with a correlation coefficient of 0.98.Conclusions: Growth effects appear to be nonlinearly related to CS exposure; therefore, no-effect exposure should be possible for CSs with low systemic exposure. Growth inhibition appears unlikely to occur in the absence of detectable reductions in cortisol concentrations. Copyright (C) 2004 Excerpta Medica, Inc.