uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
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
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.
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
Place, publisher, year, edition, pages
2015. Vol. 42, no 3, 211-224 p.
National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-221417DOI: 10.1007/s10928-015-9410-8ISI: 000354492800002PubMedID: 25792005OAI: oai:DiVA.org:uu-221417DiVA: diva2:711692
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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Kågedal, MattsKarlsson, MatsHooker, Andrew C

Search in DiVA

By author/editor
Kågedal, MattsKarlsson, MatsHooker, Andrew C
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Journal of Pharmacokinetics and Pharmacodynamics
Pharmacology and Toxicology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 548 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf