Premium
Pharmacokinetic–pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects
Author(s) -
Aymard Guy,
Berlin Ivan,
De Brettes Benoît,
Diquet Bertrand
Publication year - 2003
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2003.00152.x
Subject(s) - pharmacokinetics , cmax , chemistry , pharmacodynamics , crossover study , endocrinology , absorption (acoustics) , apomorphine , medicine , receptor , agonist , biochemistry , placebo , materials science , alternative medicine , pathology , composite material
Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D 2 receptors (DRD 2 ). 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 μ 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 E max 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 AUC 0→∞ and C max (normalised to the dose 1 μ g/kg), t 1/2 α and t 1/2 β . 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). E max values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC 50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 μ 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 E max PD model, respectively.