Pharmacokinetic–pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects

Abstract

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.

Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence

“…Despite the fact that the ACT is a well-established paradigm for indirect assessment of sensitivity of postsynaptic DA D 2 receptors, one could argue that the results measured by the ACT only assess the functional state of the tuberoinfundibular system (Lal 1988;Aymard et al 2003). As changes in the tuberoinfundibular system do not represent a neurobiological basis of addictive behavior, the correlation of the GH response with severity of dependence and with nicotine exposure we found can hardly be explained by an isolated alteration of this system.…”

“…This might indicate a reduced sensitivity of central DA receptors due to smoking. Since the apomorphine-induced GH response is primarily mediated by DA D 2 receptors in the tuberoinfundibular system (Aymard et al 2003), this could be due to a reduced density or affinity of the DA D 2 receptors, or an altered signal transduction. Furthermore, the sensitivity of central DA D 2 receptors was inversely correlated with cotinine serum levels.…”

“…The growth hormone (GH)-releasing effect of APO is mediated by DA D 2 receptors because selective stimulation of DA D 1 receptors does not lead to GH secretion (Fabbrini et al 1988). Stimulation of hypothalamic DA D 2 receptors leads to GH-releasing hormone (GHRH) secretion and consecutive GH secretion in the pituitary (Aymard et al 2003). Therefore, the amount of the apomorphine-induced GH secretion is an indicator of sensitivity of postsynaptic DA D 2 receptors.…”

The Utility of 11C-Arachidonate PET to Study in vivo Dopaminergic Neurotransmission in Humans

“…Besides the single subject who experienced bradycardia and hypotension after 20 mg/kg subcutaneous apomorphine, and who responded to intravenous hydration, no serious adverse events were observed in response to apomorphine at the doses used in this study (10 to 20 mg/kg subcutaneous). Previous studies have reported minor side effects including somnolence, nausea, dizziness, and hallucinations in response to apomorphine (Aymard et al, 2003;Bowron, 2004;Menon and Stacy, 2007). To prevent apomorphine-induced nausea during the PET proto-col, we premedicated study participants with the antiemetic trimethobenzamide (Bowron, 2004).…”

Apomorphine‐Induced Growth Hormone Response Is Attenuated by Ethanol but Not Dextromethorphan

“…In humans, the stimulation of GH secretion upon administration of the dopamine (DA) receptor agonist apomorphine (APO) is widely used to assess the functional state of the tuberoinfundibular system and of postsynaptic DA receptor (DR) function (Aymard et al, 2003). Apomorphine is an unselective DR agonist acting primarily at the postsynaptic DR D 2 receptor subtype, thereby directly stimulating GH release via pituitary DR D 2 receptors or indirectly by GHRH (Aymard et al, 2003). Several studies investigated APO‐induced GH secretion in alcoholic subjects after 2 or 3 months of abstinence and found that the GH response was reduced compared with healthy controls (e.g., Dettling et al, 1995).…”