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The pharmacodynamic effects of a dopamine-somatostatin chimera agonist on the cardiovascular system

Joost van Esdonk, M., Stevens, J., Stuurman, F. E., de Boon, W. M. I., Dehez, M., Hein van der Graaf, P. & Burggraaf, J., 1-Aug-2019, In : Journal of Cardiovascular Pharmacology. 74, 2, p. 128-136 17 p.

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  • The pharmacodynamic effects of a dopamine-somatostatin chimera agonist on the cardiovascular system

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DOI

  • Michiel Joost van Esdonk
  • Jasper Stevens
  • Frederik E Stuurman
  • Wadim M I de Boon
  • Marion Dehez
  • Piet Hein van der Graaf
  • Jacobus Burggraaf

The quantification of the effect of pharmacological treatment on the cardiovascular system is complicated due to the high level of inter-individual 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 two 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 due to 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 inter-individual 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.

Original languageEnglish
Pages (from-to)128-136
Number of pages17
JournalJournal of Cardiovascular Pharmacology
Volume74
Issue number2
Early online date11-Jul-2019
Publication statusPublished - 1-Aug-2019

ID: 90826134