Kildemoes Rasmus J, Backeljauw Philippe F, Højby Michael, Blair Joanne C, Miller Bradley S, Mori Jun, Lyauk Yassine K
Clinical Drug Development, Novo Nordisk A/S, Søborg 2860, Denmark.
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
J Endocr Soc. 2023 Sep 11;7(11):bvad115. doi: 10.1210/jendso/bvad115. eCollection 2023 Oct 9.
Growth hormone (GH) replacement therapy improves longitudinal growth and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor (IGF)-I release, the biomarker used for monitoring GH activity during treatment.
This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared with daily GH in children with GHD.
Analyses included dosing information and 1473 pharmacokinetic samples from 210 somapacitan-treated pediatric patients with GHD across 3 trials, including phase 1 (NCT01973244), phase 2 (NCT02616562; REAL 3), and phase 3 (NCT03811535; REAL 4), as well as 1381 IGF-I samples from 186 patients with GHD treated with somapacitan in REAL 3 and REAL 4. Pharmacokinetic/pharmacodynamic modeling to characterize somapacitan dose-IGF-I response and predict the response to dosing day changes.
Relationships were established between somapacitan dose, exposure, change from baseline IGF-I SD score (SDS), and height velocity (HV). A linear model permitted the development of a tool to calculate estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool requires knowledge of somapacitan injection timing relative to IGF-I sample collection timing. IGF-I SDS simulations support flexible dosing day changes while maintaining at least 4 days between doses.
We characterized the dose-IGF-I response of somapacitan in children with GHD. To support physicians in IGF-I monitoring, we present a practical guide about expected weekly average IGF-I concentrations in these patients and provide insights on dosing day flexibility.
生长激素（GH）替代疗法可改善生长激素缺乏症（GHD）儿童的纵向生长和成人身高。GH刺激胰岛素样生长因子（IGF）-I释放，IGF-I是治疗期间用于监测GH活性的生物标志物。
本研究旨在基于模型深入了解新型长效GH索马普坦与每日GH相比，在GHD儿童中剂量-IGF-I的反应。
分析包括来自3项试验中210例接受索马普坦治疗的GHD儿科患者的给药信息和1473份药代动力学样本，这些试验包括1期（NCT01973244）、2期（NCT02616562；REAL 3）和3期（NCT03811535；REAL 4），以及来自REAL 3和REAL 4中186例接受索马普坦治疗的GHD患者的1381份IGF-I样本。进行药代动力学/药效学建模以表征索马普坦剂量-IGF-I反应并预测给药日变化的反应。
建立了索马普坦剂量、暴露量、基线IGF-I标准差评分（SDS）变化和身高增长速度（HV）之间的关系。线性模型有助于开发一种工具，可根据在稳态下索马普坦给药间隔内任何时间获得的单个IGF-I样本计算估计的每周平均IGF-I暴露量。实际上，使用此工具需要了解索马普坦注射时间与IGF-I样本采集时间的关系。IGF-I SDS模拟支持灵活改变给药日，同时保持剂量间隔至少4天。
我们表征了索马普坦在GHD儿童中的剂量-IGF-I反应。为了在IGF-I监测方面为医生提供支持，我们提供了一份关于这些患者预期每周平均IGF-I浓度的实用指南，并提供了关于给药日灵活性的见解。
