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An agonist-antagonist interaction model for prolactin release following risperidone and paliperidone treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2009 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 85, no 4, 409-417 p.Article in journal (Refereed) Published
Abstract [en]

A mechanistic pharmacokinetic/pharmacodynamic model is presented, characterizing the time course of prolactin in healthy as well as schizophrenic subjects following the administration of various doses and formulations of the antipsychotic drugs risperidone and paliperidone. Prolactin concentrations from nine studies (1,462 subjects) were analyzed in NONMEM. A competitive agonist-antagonist interaction model described the competition between these drugs and dopamine for the D(2) receptors that regulate prolactin release. Tolerance development was explained by a feedback loop with prolactin stimulating dopamine release, whereas models wherein tolerance is described in terms of depletion of a prolactin pool did not explain the data well. The diurnal prolactin rhythm was described by a two-period cosine function. Baseline prolactin was health-status dependent and higher in women than in men, although the drug-induced release was less than proportional to baseline. This quantitative mechanism-based model is the first to describe prolactin release in patients, and it confirms that paliperidone and risperidone have similar potencies for prolactin release.

Place, publisher, year, edition, pages
2009. Vol. 85, no 4, 409-417 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-120661DOI: 10.1038/clpt.2008.234ISI: 000264455300018PubMedID: 19109590OAI: oai:DiVA.org:uu-120661DiVA: diva2:303776
Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2017-12-12Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 161
Keyword
population modeling, schizophrenia, D2-antagonists, pharmacodynamics, drug development
National Category
Pharmaceutical Sciences
Identifiers
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)
Opponent
Supervisors
Available from: 2012-05-03 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved

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