WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Prolactin response is a common side effect of antipsychotic drugs. • The pool model was proposed to describe the effect of remoxipride on prolactin.• The agonist-antagonist interaction (AAI) model, which incorporated a dopamine-prolactin feedback loop mechanism and circadian rhythm, was used to depict the effects of risperidone and paliperidone on prolactin. • The pool model could not characterize prolactin response in clinical studies of risperidone and paliperdone. WHAT THIS STUDY ADDS• The AAI model and the pool model were both reconstructed based on the remoxipride data set from which the original pool model was built. The pool model was extended with a circadian rhythm component which was employed in the AAI model. • The objective function values calculated by NONMEM revealed that the pool model with a circadian rhythm component best fitted the data. However, predictive checks of both models were satisfactory and the AAI model was superior in describing the circadian rhythm in healthy male volunteers when compared with earlier studies.• This study shows that the AAI model was superior as it worked well across different populations, study designs and drugs. AIMSThe tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built. METHODSThe remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM. RESULTSAccording to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well. CONCLUSIONSAccording to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time.
1 The prolactin response following administration of the D2-dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3 TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.
The D2-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3, 5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration.
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