title: A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats.
abstract: We compared the model performance of two semi-mechanistic pharmacokinetic-pharmacodynamic models, the precursor pool model and the agonist-antagonist interaction model, to describe prolactin response following the administration of the dopamine D2 receptor antagonists risperidone, paliperidone or remoxipride in rats. The time course of pituitary dopamine D2 receptor occupancy was also predicted. Male Wistar rats received a single dose (risperidone, paliperidone, remoxipride) or two consecutive doses (remoxipride). Population modeling was applied to fit the pool and interaction models to the prolactin data. The pool model was modified to predict the time course of pituitary D2 receptor occupancy. Unbound plasma concentrations of the D2 receptor antagonists were considered the drivers of the prolactin response. Both models were used to predict prolactin release following multiple doses of paliperidone. Both models described the data well and model performance was comparable. Estimated unbound EC50 for risperidone and paliperidone was 35.1nM (relative standard error 51%) and for remoxipride it was 94.8nM (31%). KI values for these compounds were 11.1nM (21%) and 113nM (27%), respectively. Estimated pituitary D2 receptor occupancies for risperidone and remoxipride were comparable to literature findings. The interaction model better predicted prolactin profiles following multiple paliperidone doses, while the pool model predicted tolerance better. The performance of both models in describing the prolactin profiles was comparable. The pool model could additionally describe the time course of pituitary D2 receptor occupancy. Prolactin response following multiple paliperidone doses was better predicted by the interaction model.
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Amit
authors.initials: A
authors.lastname: Taneja
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Dymphy R H
authors.initials: DRH
authors.lastname: Huntjens
authors.affiliation: Department of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Department of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, The Netherlands.
authors.forename: Elizabeth C M
authors.initials: ECM
authors.lastname: De Lange
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. Electronic address: j.h.proost@rug.nl.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
mesh_terms: D000818:Animals; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D011388:Prolactin
keywords: Agonist-antagonist interaction model; Dopamine D(2) receptor antagonists; Paliperidone (PubChem CID: 115237); Precursor pool model; Prolactin; Receptor occupancy; Remoxipride (PubChem CID: 54477); Risperidone (PubChem CID: 5073)