Abstract
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 [EMAX] = − 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 (EMAX = − 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.
Highlights
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
The pituitary is a key endocrine gland that produces a wide variety of hormones, including growth hormone (GH) and prolactin (PRL) [1]
Summary
The pituitary is a key endocrine gland that produces a wide variety of hormones, including growth hormone (GH) and prolactin (PRL) [1]. A pituitary adenoma causes disruption in the highly regulated mechanisms that control the stimulation and inhibition of GH [2]. Pituitary adenomas cause severe GH hypersecretion [3, 4] and may lead to an excessive release of PRL in 20–30% of patients [2, 4]. A placebo-controlled single ascending and multiple ascending dose phase I clinical trial was performed to study the pharmacokinetics (PK), safety and tolerability of BIM23B065 in healthy male volunteers [5]. BIM230B065 belongs to the novel class of dopastatins, which concurrently target somatostatin and dopamine receptors and is under investigation for the treatment of neuro-endocrine tumors [6].
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