Global Development, Novo Nordisk A/S, Bagsvaerd, Denmark.
Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Eur J Endocrinol. 2022 May 16;187(1):27-38. doi: 10.1530/EJE-21-1167.
Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose-responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose-insulin-like growth factor I (IGF-I) responses in AGHD patients.
Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.
Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose-IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.
The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7-9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3-4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose-exposure-IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.
This study extends the knowledge of the somapacitan dose-IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.
由于患者间剂量反应存在差异，成人生长激素缺乏症（AGHD）患者的生长激素（GH）替代疗法需要个体化滴定。本研究旨在根据 AGHD 患者中 somapacitan 剂量-胰岛素样生长因子 I（IGF-I）反应的分析结果，为新型长效 GH 衍生物 somapacitan 的剂量和滴定提供临床指导。
对 330 例接受 somapacitan 治疗的 AGHD 患者的 3 项 3 期临床试验中的给药信息、4364 份 somapacitan 浓度样本和 4880 份 IGF-I 样本进行分析。
采用药代动力学/药效动力学模型，根据年龄和口服雌激素治疗情况评估起始剂量组，描述总体 AGHD 人群和患者亚组的剂量-IGF-I 反应，预测剂量变化的 IGF-I 反应并模拟漏用剂量。
分析结果支持对年轻患者和接受口服雌激素替代疗法的女性给予较高起始剂量的临床建议。对于从每日 GH 治疗转为 somapacitan 治疗的患者，somapacitan（mg/周）与 somatropin（mg/天）的维持剂量比预计为 8.2（观察到的四分位距为 6.7-9.1）。IGF-I SDS 曲线模拟结果证实，somapacitan 给药后 3-4 天取样是 IGF-I 检测的适当时间，并支持在漏用剂量的情况下，最多可延迟 3 天给药。亚组分析描述了患者亚组中剂量-暴露-IGF-I 反应，表明剂量需求主要受性别和口服雌激素治疗的影响。
本研究扩展了 somapacitan 剂量-IGF-I 反应的知识，并提供了 AGHD 患者每周一次 somapacitan 临床给药剂量的信息。
