The Pharmacodynamic Effects of a Dopamine-Somatostatin Chimera Agonist on the Cardiovascular System

The quantification of the effect of pharmacological treatment on the cardiovascular system is complicated because of the high level of interindividual and circadian variability. Recently, a dopamine-somatostatin chimera, BIM23B065, was under investigation to concurrently target the somatostatin and dopamine D2 receptors for the treatment of neuroendocrine tumors. However, both dopamine and somatostatin interact with different components of the cardiovascular system. This study established the response of the heart rate and the systolic blood pressure after administration of BIM23B065 in healthy male volunteers by analysis of the rate-pressure product (RPP), in a model-informed analysis. The RPP in the supine position of placebo-treated subjects showed a clear circadian component, best described by 2 cosine functions. The pharmacokinetics of BIM23B065 and its metabolite were best described using 2-compartment models with different forms of elimination kinetics. The administration of BIM23B065 gave a statistically significant reduction in the RPP, after which the effect diminished because of the tolerance to the cardiovascular effects after prolonged exposure to BIM23B065. This model provided insight in the circadian rhythm of the RPP in the supine position and the level of interindividual variability in healthy male volunteers. The developed population pharmacokinetic/pharmacodynamic model quantified the interaction between BIM23B065 and the RPP, informing on the clinical pharmacological properties of BIM23B065.