title: Predictions of in vivo prolactin levels from in vitro K(i) values of D(2) receptor antagonists using an agonist-antagonist interaction model.
abstract: Prolactin elevation is a side effect of all currently available D(2) receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D(2) effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess the correlation between in vitro estimates of D(2) receptor affinity and pharmacokinetic-pharmacodynamic model-based estimates obtained from analysis of clinical data using an agonist-antagonist interaction (AAI) model and to assess the value of such a correlation in early prediction of full prolactin time profiles. A population model describing longitudinal prolactin data was fitted to clinical data from 16 clinical phases 1 and 3 trials including five different compounds. Pharmacokinetic data were modeled for each compound and the prolactin model was both fitted in per-compound fits as well as simultaneously to all prolactin data. Estimates of prolactin elevating potency were compared to corresponding in vitro values and their predictability was evaluated through model-based simulations. The model successfully described the prolactin time course for all compounds. Estimates derived from experimental preclinical data and the model fit of the clinical data were strongly correlated (p<0.001), and simulations adequately predicted the prolactin elevation in five out of six compounds. The AAI model has the potential to be used in drug development to predict prolactin response for a given exposure of D(2) antagonists using routinely produced preclinical data.
authors: Department of Pharmaceutical Biosciences, Uppsala University, Box 591751 24, Uppsala, Sweden. klas.petersson@qpharmetra.com
authors: Klas J
authors: KJ
authors: Petersson
authors: An M
authors: AM
authors: Vermeulen
authors: Lena E
authors: LE
authors: Friberg
mesh_terms: D001667:Binding, Competitive; D015415:Biomarkers / Q000097:blood; D017321:Clinical Trials, Phase I as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004298:Dopamine / Q000097:blood*; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D006966:Hyperprolactinemia / Q000097:blood / Q000139:chemically induced*; D008954:Models, Biological; D011388:Prolactin / Q000097:blood*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C581293:DRD2 protein, human; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D011388:Prolactin; D004298:Dopamine
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