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Nonlinear Mixed Effects Methods for Improved Estimation of Receptor Occupancy in PET Studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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 [en]
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: urn:nbn:se:uu:diva-222498ISBN: 978-91-554-8942-7 (print)OAI: oai:DiVA.org:uu-222498DiVA: diva2:712075
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
List of papers
1. Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers
Open this publication in new window or tab >>Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers
Show others...
2012 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 61, no 4, 849-856 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain.

AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed.

The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200nM. The density of the receptor binding sites was estimated to 800nM and 200nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.

Keyword
Nonlinear mixed effects modelling, Positron emission tomography, Receptor occupancy, [11C]AZD9272, mGluR5 receptor
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-172214 (URN)10.1016/j.neuroimage.2012.02.085 (DOI)000305920600012 ()22425672 (PubMedID)
Available from: 2012-04-02 Created: 2012-04-02 Last updated: 2017-12-07
2. A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
Open this publication in new window or tab >>A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
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2013 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 82, 160-169 p.Article in journal (Refereed) Published
Abstract [en]

AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

Keyword
Nonlinear mixed effects modelling, Positron emission tomography, Receptor occupancy, [C-11]-ABP688, mGluR5 receptor
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-209453 (URN)10.1016/j.neuroimage.2013.05.006 (DOI)000324568400018 ()
Available from: 2013-10-24 Created: 2013-10-21 Last updated: 2017-12-06
3. 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.
Open this publication in new window or tab >>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.
(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:nbn:se:uu:diva-221411 (URN)
Available from: 2014-04-11 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
4. Improved precision of exposure-response relationships by optimal dose-selection. Examples from studies of receptor occupancy using PET and dose finding for neuropathic pain treatment
Open this publication in new window or tab >>Improved precision of exposure-response relationships by optimal dose-selection. Examples from studies of receptor occupancy using PET and dose finding for neuropathic pain treatment
2015 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 42, no 3, 211-224 p.Article in journal (Refereed) Published
National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-221417 (URN)10.1007/s10928-015-9410-8 (DOI)000354492800002 ()25792005 (PubMedID)
Available from: 2014-04-11 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved

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