Global Development, Novo Nordisk A/S, 2860, Søborg, Denmark.
Department of Pharmacometrics, Novartis, Basel, Switzerland.
Clin Pharmacokinet. 2021 Sep;60(9):1217-1226. doi: 10.1007/s40262-021-01011-3. Epub 2021 Apr 17.
Once-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency.
A model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model.
The model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children.
The pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age.
Pooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783.
NCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.
每日一次注射用重组人生长激素（GH）制剂（如诺和诺德公司的 Norditropin）用于治疗儿童和成人的 GH 缺乏症，其大部分治疗效果是通过胰岛素样生长因子-I（IGF-I）反应介导的。尽管这种治疗方法已经使用了很长时间，但关于其药代动力学和药效学（血清 IGF-I 反应）的数据很少，也很少有关于儿童和成人 GH 药代动力学/药效学（PK/PD）效应关系潜在差异的数据。本研究旨在描述成人和儿童 GH 缺乏症患者每日皮下注射 GH 后的 GH 药代动力学和 IGF-I 特征。
基于三项 I 期临床试验（两项使用 Norditropin 作为 somapacitan 的比较药物，一项作为聚乙二醇化 GH 产品的比较药物）的人群 PK/PD 建模荟萃分析，建立了一个模型。首先进行了一个模型的构建，该模型能够描述 GH 的药代动力学。然后使用 PK 和 PD 数据开发了 IGF-I 数据的 PD 模型，并将所有 PK 参数固定为 PK 模型中估计的值。
该模型能够准确描述和预测 GH 的药代动力学和 IGF-I 反应。体重被证明对 GH 暴露（和 IGF-I 标准差评分）有重要的负相关影响，这在很大程度上解释了成人和儿童之间的差异。
这里开发的药代动力学/药效学可以为不同体重的 GH 缺乏症患者不同剂量的 GH 的 PD 效应提供预期，无论其年龄如何。
ClinicalTrials.gov 标识符 NCT01973244、NCT00936403 和 NCT01706783 数据的汇总建模分析。
NCT01973244：2013 年 10 月 22 日；NCT00936403：2009 年 7 月 9 日；NCT01706783：2012 年 10 月 11 日。
