Sheehan John J, Reilly Kristin R, Fu Dong-Jing, Alphs Larry
Bristol-Myers Squibb, Plainsboro, New Jersey, USA.
Innov Clin Neurosci. 2012 Jul;9(7-8):17-23.
Small peak-to-trough drug levels have been suggested to be related to improved tolerability. The aim of this study is to review the steady-state, peak-to-trough, plasma-concentration fluctuation of long-acting injectable antipsychotics and equivalent oral formulations.
A review of published literature and clinical study reports identified references that reported, depicted, or permitted derivation of the steady-state, peak-to-trough, plasma-concentration fluctuation of antipsychotics (the ratio of maximum concentration to minimum concentration following administration according to the recommended dosing interval) over the dosing interval. Suitable references were identified for haloperidol decanoate, olanzapine pamoate, paliperidone palmitate, risperidone long-acting injectable, and zuclopenthixol decanoate and their oral equivalents except zuclopenthixol. The single-dose time to maximum plasma concentration (T(max)) and half-life (t(1/2)) were also identified.
The steady-state, peak-to-trough, plasma-concentration ratios of oral antipsychotics varied from 1.47 (paliperidone extended-release, once daily) to 3.30 (active-moiety risperidone, once daily). Among long-acting injectable antipsychotics, the ratios varied from 1.56 (paliperidone palmitate, once monthly) to approximately 4 (olanzapine pamoate, once every four weeks). Among drugs with similar dosing intervals, longer T(max) and/or t(1/2) generally correlated with less peak-to-trough fluctuation.
Peak-to-trough fluctuations in plasma concentrations vary widely and may be affected by differences in dosing, pharmacokinetic sampling, subjects' phenotypes, concomitant medications, comorbid diseases, and formulation. These fluctuations may affect clinical response and tolerability. Along with other patient-specific and drug-specific factors, these fluctuations warrant consideration when selecting an antipsychotic and antipsychotic formulation. Further study is needed with more robust and generalizable peak-to-trough fluctuation data.
药物的小峰谷浓度差被认为与耐受性的改善有关。本研究的目的是回顾长效注射用抗精神病药物及其等效口服制剂的稳态、峰谷和血浆浓度波动情况。
对已发表的文献和临床研究报告进行综述，确定那些报告、描述或允许推导抗精神病药物在给药间隔内的稳态、峰谷和血浆浓度波动情况（根据推荐给药间隔给药后最大浓度与最小浓度之比）的参考文献。确定了氟哌啶醇癸酸酯、奥氮平棕榈酸酯、帕利哌酮棕榈酸酯、长效注射用利培酮和癸酸珠氯噻醇及其除珠氯噻醇外的口服等效物的合适参考文献。还确定了单剂量达最大血浆浓度时间（T(max)）和半衰期（t(1/2)）。
口服抗精神病药物的稳态、峰谷血浆浓度比在1.47（帕利哌酮缓释片，每日一次）至3.30（活性成分利培酮，每日一次）之间变化。在长效注射用抗精神病药物中，该比值在1.56（帕利哌酮棕榈酸酯，每月一次）至约4（奥氮平棕榈酸酯，每四周一次）之间变化。在给药间隔相似的药物中，较长的T(max)和/或t(1/2)通常与较小的峰谷波动相关。
血浆浓度的峰谷波动差异很大，可能受到给药方式、药代动力学采样、受试者表型、合并用药、合并疾病和制剂等因素的影响。这些波动可能影响临床反应和耐受性。在选择抗精神病药物和抗精神病药物制剂时，除了其他患者特异性和药物特异性因素外，这些波动也值得考虑。需要通过更可靠和可推广的峰谷波动数据进行进一步研究。
