Publication Date:
2012-11-12
Description:
ABSTRACT 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. Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0906-2 Authors Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Su Jin Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Yook-Hwan Noh, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Byung Chul Lee, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Seok-Joon Jin, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Hyun Soo Park, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Soohyeon Kim, Clinical Trial Center, Asan Medical Center, Seoul, Republic of Korea In-Jin Jang, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea Sang Eun Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741
Print ISSN:
0724-8741
Electronic ISSN:
1573-904X
Topics:
Chemistry and Pharmacology
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