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_MAX] = − 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_MAX = − 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.

中文翻译：

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使用群体 PK/PD 模型量化生长抑素-多巴胺嵌合体的内源性生长激素和催乳素降低作用。

使用生长抑素-多巴胺嵌合体 (BIM23B065) 在健康男性志愿者中进行了 1 期临床试验，从中可以获得有关抑制脉动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告知群体药效学建模方法分析内源性生长激素谱，该方法是为分析脉动谱而开发的。使用具有催乳素释放的昼夜节律成分的群体池模型对催乳素浓度进行建模。在用 BIM23B065 治疗期间，生长激素分泌显着减少（最大效果 [E _MAX] = − 64.8%)，在三个多剂量递增队列中的两个队列中，脉冲频率显着降低。确定了催乳素分泌中的昼夜节律成分，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 _MAX  = - 91%）催乳素的释放，并证明在给药多天后催乳素分泌进一步减少。本研究量化了 BIM23B065 对两种垂体激素释放的浓度效应关系，为 BIM23B065 的嵌合作用提供了药理学证据。