Comparison of the agonist‐antagonist interaction model and the pool model for the effect of remoxipride on prolactin

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. AIMS The 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. METHODS The 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. RESULTS According 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. CONCLUSIONS According to the analysis performed