An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.
An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.
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先天性肾上腺增生儿童皮质醇、17-羟孕酮和雄烯二酮生物标志物的综合PK-PD模型
DOI：
10.1111/bcp.14470
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发表时间：
2021-03
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
本研究的目的是描述皮质醇与肾上腺生物标志物17-羟孕酮和雄烯二酮在先天性肾上腺增生（CAH）儿童中的药代动力学/药效学关系。使用非线性混合效应建模方法分析CAH儿童（n = 50）在6小时内获得的皮质醇、17-羟孕酮和雄烯二酮浓度。昼夜节律是明显的，该模型利用了未经治疗的CAH儿童昼夜节律的文献信息。间接响应模型，其中皮质醇抑制生产率的所有三种化合物使用的I最大模型。皮质醇通过一室模型表征，表观清除率和分布容积估计值分别为22.9 L/h/70 kg和41.1 L/70 kg。皮质醇、17-羟孕酮和雄烯二酮的皮质醇浓度IC50值估计分别为1.36、0.45和0.75 μ g/dL。发现对17 OHP的抑制作用比D4A更有效，并且在盐消耗受试者中的IC50值高于简单的男性化剂。皮质醇、17-羟孕酮和雄烯二酮的产生率在单纯男性化受试者中较高。皮质醇、17-羟孕酮和雄烯二酮的半衰期分别为60、47和77分钟。快速变化的生物标志物对皮质醇浓度的反应突出表明，单次测量提供了有关儿童疾病控制的不稳定信息。我们的模型密切捕获了观察到的皮质醇、17-羟孕酮和雄烯二酮浓度。它可用于预测24小时内的浓度，并允许计算许多新的暴露指标，例如，AUC、AUC高于阈值、时间在范围内等。我们的长期目标是揭示剂量-暴露-结果关系，临床医生可以使用这些关系来调整氢化可的松剂量和时间。
The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17‐hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). A nonlinear mixed‐effect modelling approach was used to analyse cortisol, 17‐hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an I max model. Cortisol was characterized by a one‐compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17‐hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt‐wasting subjects than simple virilizers. Production rates of cortisol, 17‐hydroxyprogesterone and androstenedione were higher in simple‐virilizer subjects. Half‐lives of cortisol, 17‐hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17‐hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC‐above‐threshold, time‐within‐range, etc. Our long‐range goal is to uncover dose–exposure–outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.
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影响因子：
4
作者：
LOW, SC;CHAPMAN, KE;SECKL, JR
通讯作者：
SECKL, JR
DOI：
10.1023/a:1020678628317
发表时间：
1999-02-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
Chakraborty, A;Krzyzanski, W;Jusko, WJ
通讯作者：
Jusko, WJ
影响因子：
5.8
作者：
Charmandari, E;Hindmarsh, PC;Brook, CGD
通讯作者：
Brook, CGD
影响因子：
5.2
作者：
FRISCH, H;PARTH, K;SWOBODA, W
通讯作者：
SWOBODA, W
影响因子：
9.8
作者：
GHIZZONI, L;BERNASCONI, S;GIOVANNELLI, G
通讯作者：
GIOVANNELLI, G