caa a22 4500 605533881 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10928-015-9410-8 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9410-8 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 [Elektronische Daten] [Matts Kågedal, Mats Karlsson, Andrew Hooker] An understanding of the relationship between drug exposure and response is a fundamental basis for any dosing recommendation. We investigate optimal dose-selection for two different types of studies, a receptor occupancy study assessed by positron emission tomography (PET) and a dose-finding study in neuropathic pain treatment. For the PET-study, an inhibitory E-max model describes the relationship between drug exposure and displacement of a radioligand from specific receptors in the brain. The model has a mechanistic basis in the law of mass action and the affinity parameter (Ki PL ) is of primary interest. For optimization of the neuropathic pain study, the model is empirical and the exposure response curve itself is of primary interest. An alternative parameterization of the sigmoid Emax model was therefore used where the plasma concentration corresponding to the minimum relevant efficacy was estimated as a parameter. Optimal design methodology was applied using the D-optimal criterion as well as the Ds-optimal criterion where parameters of interest were defined. For the PET-study it was shown that the precision of Ki PL can be improved by inclusion of brain regions with both high and low receptor density and that the need for high doses is reduced when a brain region with low receptor density is included in the analysis. In the case of the neuropathic pain study it was shown that a Ds-optimal study design using the reparameterized Emax model can improve the precision in the minimum effective dose compared to a D-optimal design. Springer Science+Business Media New York, 2015 Dose finding nationallicence Exposure response nationallicence Optimal design nationallicence PET nationallicence Kågedal Matts Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut Karlsson Mats Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut Hooker Andrew Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 211-224 1567-567X 42:3<211 2015 42 10928 https://doi.org/10.1007/s10928-015-9410-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9410-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kågedal Matts Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut NATIONALLICENCE 700 1- Karlsson Mats Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut NATIONALLICENCE 700 1- Hooker Andrew Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/3(2015-06-01), 211-224 1567-567X 42:3<211 2015 42 10928