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.

Prediction of glycaemic control in young children and adolescents with type 1 diabetes mellitus using mixed-effects logistic regression modelling.

OBJECTIVES: Glycaemic control in children and adolescents with type 1 diabetes mellitus can be challenging, complex and influenced by many factors. This study aimed to identify patient characteristics that were predictive of satisfactory glycaemic control in the paediatric population using a logistic regression mixed-effects (population) modelling approach. METHODS: The data were obtained from 288 patients aged between 1 and 22 years old recorded retrospectively over 3 years (1852 HbA1c observations). HbA1c status was categorised as 'satisfactory' or 'unsatisfactory' glycaemic control, using an a priori cut-off value of HbA1c ≥ 9% (75 mmol/mol), as used routinely by the hospital's endocrine paediatricians. Patients' characteristics were tested as covariates in the model as potential predictors of glycaemic control. RESULTS: There were three patient characteristics identified as having a significant influence on glycaemic control: HbA1c measurement at the beginning of the observation period (Odds Ratio (OR) = 0.30 per 1% HbA1c increase, 95% confidence interval (CI) = 0.20-0.41); Age (OR = 0.88 per year increase, 95% CI = 0.80-0.94), and fractional disease duration (disease duration/age, OR = 0.80 per 0.10 increase, 95% CI = 0.66-0.93) were collectively identified as factors contributing significantly to lower the probability of satisfactory glycaemic control. CONCLUSIONS: The study outcomes may prove useful for identifying paediatric patients at risk of having unsatisfactory glycaemic control, and who could require more extensive monitoring, support, or targeted interventions.