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Predictions of In Vivo Prolactin Levels from In Vitro K (i) Values of D-2 Receptor Antagonists Using an Agonist-Antagonist Interaction Model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Janssen Research & Development, a Division of Janssen Pharmaceutica, Belgium.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
2013 (English)In: AAPS Journal, ISSN 1550-7416, Vol. 15, no 2, 533-541 p.Article in journal (Refereed) Published
Abstract [en]

Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 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 D2 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 D2 antagonists using routinely produced preclinical data.

Place, publisher, year, edition, pages
2013. Vol. 15, no 2, 533-541 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-172394DOI: 10.1208/s12248-012-9450-6ISI: 000317136100025OAI: oai:DiVA.org:uu-172394DiVA: diva2:514536
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2013-05-28Bibliographically approved
In thesis
1. Population Pharmacodynamic Modeling and Methods for D2-receptor Antagonists
Open this publication in new window or tab >>Population Pharmacodynamic Modeling and Methods for D2-receptor Antagonists
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Early predictions of a potential drug candidate’s time-course of effect and side-effects, based on models describing drug concentrations, drug effects and disease progression, would be valuable to make drug development more efficient. Pharmacodynamic modeling can incorporate and propagate prior knowledge and be used for simulations of different scenarios.

In this thesis three population pharmacodynamic models were developed to describe the antipsychotic effects and the side-effects prolactin elevation and Extra Pyramidal Symptoms (EPS) following administration of D2-receptor antagonists, commonly used in the treatment of schizophrenia.

Model parameter estimates of prolactin elevating potencies of six compounds correlated with in vitro values of receptor affinities, and parameters related to diurnal prolactin variation and tolerance were similar for the different compounds. The developed prolactin model can thereby be used to predict the time-course of prolactin elevation in patients for a drug candidate using information on in vitro affinity to the D2-receptor. Furthermore, the clinical antipsychotic effect and the prolactin elevation was found to correlate on the individual level for the three antipsychotic compounds investigated and a quantitative relation between D2-receptor occupancy in the brain and prolactin elevation was established. These results support the use of prolactin concentrations as a biomarker in drug development or for individual dose adjustments in clinical care.

The developed model for spontaneously reported EPS adverse events, following treatment with one of five antipsychotics drugs, characterized both the duration and severity of EPS. The model successfully described both the proportions and number of transitions between severity grades and was shown to adequately simulate longitudinal categorical EPS data.

Complex pharmacodynamic models are often associated with long estimation times and non-normal distributions of individual parameters. A method for shortening computation times by substituting differential equations for difference equations was evaluated and shown to be valuable for some models. In addition, transformation of distributions allowed for non-normal distributions of between-subject variability to be better characterized and thereby simulation properties were improved.

In conclusion, population pharmacodynamic models for a range of D2-receptor antagonists were developed and together with the investigated methods the models can facilitate prediction of effects and side-effects in drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 69 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 161
population modeling, schizophrenia, D2-antagonists, pharmacodynamics, drug development
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-172540 (URN)978-91-554-8346-3 (ISBN)
Public defence
2012-05-25, B41, Biomedicinskt Centrum, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2012-05-03 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved

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