Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and...

An integrated pharmacokinetic-pharmacodynamic model is suggested for remoxipride and its effect on prolactin (PRL) release acting by preventing the inhibitory effect of dopamine D2 receptors in the anterior pituitary. The model was implemented to describe the time course of PRL plasma levels after administration of two consecutive doses of remoxipride at 5 different time intervals, 2, 8, 12, 24 and 48 hr. The model used is an indirect response model. It consists of three parts: 1) the pharmacokinetics of remoxipride; 2) a physiological substance model for PRL, incorporating the synthesis of PRL and its release into and elimination from plasma; and 3) a pharmacodynamic model describing the influence of remoxipride on the PRL release from the pool. A linear pharmacodynamic model gave the best description of the time course of PRL. The limitation in the PRL release is the amount available in the pool, which takes 24 to 48 hr to fully restore, rather than a maximal effect of remoxipride. The intra- and interindividual variability of remoxipride as well as of the PRL response was low.