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Extension of the simplified reference tissue model, to allow different non-specific concentrations in the brain region of interest and the reference region. Application to PET with the radioligand [11C]AZ10419369 displaced by AZD3783 at the serotonin 5HT1B receptor.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
(English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572Article in journal (Other academic) Submitted
National Category
Medical and Health Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-221411OAI: oai:DiVA.org:uu-221411DiVA: diva2:711694
Available from: 2014-04-11 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
Open this publication in new window or tab >>Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Receptor occupancy assessed by Positron Emission Tomography (PET) can provide important translational information to help bridge information from one drug to another or from animal to man. The aim of this thesis was to develop nonlinear mixed effects methods for estimation of the relationship between drug exposure and receptor occupancy for the two mGluR5 antagonists AZD9272 and AZD2066 and for the 5HT1B receptor antagonist AZD3783. Also the optimal design for improved estimation of the relationship between drug exposure and receptor occupancy as well as for improved dose finding in neuropathic pain treatment, was investigated.

Different modeling approaches were applied. For AZD9272, the radioligand kinetics and receptor occupancy was simultaneously estimated using arterial concentrations as input function and including two brain regions of interest. For AZD2066, a model was developed where brain/plasma partition coefficients from ten different brain regions were included simultaneously as observations. For AZD3783, the simplified reference tissue model was extended to allow different non-specific binding in the reference region and brain regions of interest and the possibility of using white matter as reference was also evaluated. The optimal dose-selection for improved precision of receptor occupancy as well as for improved precision of the minimum effective dose of a neuropathic pain treatment was assessed, using the D-optimal as well as the Ds-optimal criteria.

Simultaneous modelling of radioligand and occupancy provided a means to avoid simplifications or approximations and provided the possibility to tests or to relax assumptions. Inclusion of several brain regions of different receptor density simultaneously in the analysis, markedly improved the precision of the affinity parameter. Higher precision was achieved in relevant parameters with designs based on the Ds compared to the D-optimal criterion. The optimal design for improved precision of the relationship between dose and receptor occupancy depended on the number of brain regions and the receptor density of these regions.

In conclusion, this thesis presents novel non-linear mixed effects models estimating the relationship between drug exposure and receptor occupancy, providing useful translational information, allowing for a better informed drug-development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 188
Keyword
PET, positron emission tomography, receptor occupancy, nonlinear mixed effects, NONMEM, optimal design, dose finding
National Category
Medical and Health Sciences Bioinformatics (Computational Biology)
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-222498 (URN)978-91-554-8942-7 (ISBN)
Public defence
2014-06-05, B41, Uppsala Biomedicinska Centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2014-05-14 Created: 2014-04-11 Last updated: 2014-06-30

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