Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
J Pharmacokinet Pharmacodyn. 2020 Jun;47(3):229-239. doi: 10.1007/s10928-020-09683-3. Epub 2020 Apr 4.
A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [E] = - 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (E = - 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065.
一项在健康男性志愿者中进行的 somatostatin-dopamine 嵌合体（BIM23B065）的 1 期临床试验，可获得关于抑制脉冲式内源性生长激素和催乳素分泌的浓度-效应关系的信息。使用两步解卷积分析信息的群体药效动力学建模方法分析内源性生长激素谱，该方法是为分析脉冲式曲线而开发的。使用具有催乳素释放昼夜节律成分的群体池模型对催乳素浓度进行建模。在接受 BIM23B065 治疗期间，生长激素分泌显著减少（最大效应 [E] = -64.8%），在三个递增剂量组中的两个组中，脉冲频率也显著降低。催乳素分泌存在昼夜节律成分，使用具有 24 小时和 12 小时周期的两个余弦函数的组合进行建模。BIM23B065 的给药强烈抑制（E = -91%）催乳素的释放，并在多日给药后进一步降低催乳素的分泌。本研究定量了 BIM23B065 对两种垂体激素释放的浓度-效应关系，为 BIM23B065 的嵌合作用的药理学提供了证据。
