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

Journal of Pharmacokinetics and Pharmacodynamics
Matts KågedalAndrew C Hooker

Abstract

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 f...Continue Reading

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Citations

Apr 25, 2018·The AAPS Journal·Theodoros PapathanasiouRune Viig Overgaard
Jul 31, 2019·The AAPS Journal·Theodoros PapathanasiouAndrew C Hooker

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