Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea.
Pharm Res. 2013 Mar;30(3):683-93. doi: 10.1007/s11095-012-0906-2. Epub 2012 Nov 10.
To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development.
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.
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.
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.
评估正电子发射断层扫描（PET）测量的 D2 受体占有率（D2RO）在抗精神病药物开发中的潜在应用。
在这项随机、平行组研究中，8 名健康男性志愿者每天口服 0.5mg（n=3）、1mg（n=2）或 3mg（n=3）的氟哌啶醇，连续 7 天。在氟哌啶醇之前和第 8 天、第 12 天进行了 PET 扫描，并在第 7 天进行了连续药代动力学采样。使用 NONMEM 分析时间过程中的纹状体和尾状核的 D2 受体结合潜力和药代动力学，进行各种氟哌啶醇方案的 D2RO 时间曲线模拟，以找到最佳的给药方案。
具有饱和结合室的单室模型和效应室中的抑制 E(max)模型最好地描述了数据。半最大抑制时纹状体和尾状核中的氟哌啶醇血浆浓度分别为 0.791 和 0.650ng/ml。模拟表明氟哌啶醇 2mg 每 12 小时给药接近最佳剂量。
这项研究表明，在多次给药后的稳态药效学设计中进行稀疏的 D2RO 测量，可以揭示 D2 拮抗剂治疗效果的可能性，并通过建模和模拟确定后期临床研究的潜在最佳剂量。
