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Exploration of Optimal Dosing Regimens of Haloperidol, a D(2) Antagonist, via Modeling and Simulation Analysis in a D (2) Receptor Occupancy Study.
MedLine Citation:
PMID:  23138261     Owner:  NLM     Status:  Publisher    
PURPOSE: To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. METHODS: In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3 mg (n = 3) of haloperidol once daily for 7 days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. RESULTS: One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose. CONCLUSION: This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.
Hyeong-Seok Lim; Su Jin Kim; Yook-Hwan Noh; Byung Chul Lee; Seok-Joon Jin; Hyun Soo Park; Soohyeon Kim; In-Jin Jang; Sang Eun Kim
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-10
Journal Detail:
Title:  Pharmaceutical research     Volume:  -     ISSN:  1573-904X     ISO Abbreviation:  Pharm. Res.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea.
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