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Modeling of brain D2 receptor occupancy-plasma concentration relationships with a novel antipsychotic, YKP1358, using serial PET scans in healthy volunteers

Cited 20 time in Web of Science Cited 26 time in Scopus
Authors
Lim, K. S.; Kwon, J. S.; Jang, I. J.; Jeong, J. M.; Lee, J. S.; Kim, H. W.; Kang, W. J.; Kim, J. R.; Cho, J. Y.; Kim, E.; Yoo, S. Y.; Shin, S. G.; Yu, K. S.
Issue Date
2007-01-30
Publisher
Elsevier
Citation
Clin Pharmacol Ther. 2007 Feb;81(2):252-8.
Keywords
Administration, OralAdultAlgorithmsAlkaloids/administration & dosage/blood/pharmacokineticsAntipsychotic Agents/administration & dosage/blood/*pharmacokineticsArea Under CurveBrain/*metabolismCarbon RadioisotopesDopamine Antagonists/administration & dosage/blood/*pharmacokineticsDose-Response Relationship, DrugHalf-LifeHumansMaleModels, BiologicalPositron-Emission Tomography/*methodsReceptors, Dopamine D2/antagonists & inhibitors/*metabolism
Abstract
YKP1358 is a novel serotonin (5-HT(2A)) and dopamine (D(2)) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D(2) receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D(2) receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [(11)C]raclopride. The D(2) receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D(2) receptor occupancy by YKP1358 increased to 53-83% at 2 h, and then decreased afterwards, ranging from 40-64% at 5 h to 20-51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D(2) receptor occupancy that was well predicted by a sigmoid E(max) model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D(2) receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D(2) receptor occupancy.
ISSN
0009-9236 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17259948

http://hdl.handle.net/10371/24857
DOI
https://doi.org/10.1038/sj.clpt.6100049
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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