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- Title
PII-30.
- Authors
Lim, K. S.; Kim, J. R.; Kim, J. W.; Kim, B. H.; Kim, E. T.; Yoo, S. Y.; Kwon, J. S.; Lee, J. S.; Jung, J. M.; Park, J. S.; Koh, H. J.; Huh, J. W.; Ku, B.; Lee, J.; Choi, Y. M.; Seo, H. B.; Cho, J. Y.; Yu, K. S.; Jang, I. J.; Shin, S. G.
- Abstract
Background: YKP1358 is a novel D2 antagonist. We conducted a D2 receptor occupancy study with YKP1358 in healthy Korean male volunteers using PET, to measure the D2 occupancy and how it relates to plasma drug levels.Methods: A single oral dose, dose escalation (100, 200, 250mg) study was performed in 9 volunteers. The D2 occupancy of a putamen was measured pre-dose, 2, 5, 10h after single dosing of YKP1358. Blood samples for evaluation of plasma level were taken at pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 32 h post-dose.Results: Individual plasma concentration-time profiles of YKP1358 were fitted to a three compartment model. Tmax was 0.67 h, and elimination half-life was 5.71, 7.46, 8.58 h in each dosing groups. Cmax was 17.7 to 224 ng/ml in 100mg group. D2 occupancy was 60 - 80% at 2h, 40 - 60% at 5 h, and 20 - 50% at 10h. The relationship of plasma level and D2 occupancy of YKP1358 was well predicted by Emax model using NONMEM, and Emax was 100%, EC50 was 8.9 ng/ml.Conclusions: PK profile of YKP1358 showed individual variation, but the D2 occupancy was less variable and well predicted by an Emax model. Since D2 antagonists show therapeutic effects at 50 - 80% D2 occupancy, and the EC50 of YKP1358 is less than 10 ng/ml, doses of YKP1358 which maintain plasma concentrations above 10 ng/ml are expected to show therapeutic effects. Using these results doses for schizophrenic patients can be determined, but further evaluation is needed for confirming the PK- D2 occupancy-therapeutic effects relationship of YKP1358 in patients.Clinical Pharmacology & Therapeutics (2005) 79, P44–P44; doi: 10.1016/j.clpt.2005.12.155
- Subjects
CLINICAL trials; POSITRON emission tomography; ORAL medicine; BLOOD plasma; PHARMACEUTICAL research
- Publication
Clinical Pharmacology & Therapeutics, 2006, Vol 79, Issue 2, pP44
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.12.155