Darby John K, Pasta David J, Wilson Michael G, Herbert John
Department of Psychiatry, San Mateo County Mental Health Services, San Mateo, California, USA.
Clin Drug Investig. 2008;28(9):553-64. doi: 10.2165/00044011-200828090-00002.
Conflicting therapeutic drug monitoring (TDM) results have been reported for risperidone and olanzapine. This study set out to examine the long-term pharmacokinetics of risperidone and olanzapine in a locked skilled nursing facility where medication administration was controlled by nursing staff.
TDM was performed in a long-term treatment protocol for risperidone and olanzapine in 67 refractory chronic schizophrenic patients in a locked, skilled nursing facility. TDM was performed 632 times in the risperidone group of 34 patients and 563 times in the olanzapine group of 33 patients. The logarithm of plasma concentrations were analysed through time by piecewise linear mixed model regressions adjusted for the logarithm of dose.
We found risperidone plasma concentration/dose ratio (C/D) accumulation peaks of 49% at 2 months (from baseline concentration) and 9-hydroxy-risperidone and total moiety C/D accumulation peaks of 66% and 55% above the 2-month level at 6 months, which are somewhat similar to those found in our prior study that included a subset of data points analysed here. The risperidone conversion to 9-hydroxy-risperidone by cytochrome P450 (CYP) 2D6 suggests CYP2D6 inhibition or DNA down-regulation in the first 2 months. Olanzapine showed a C/D accumulation peak at 4 months of 31% above baseline, and a slower increase to 47% above baseline at 18 months with no clear plateau.
We identified five potential perturbations in the pharmacokinetics of risperidone and olanzapine that could potentially lead to adverse drug reactions. These long-term effects would not be captured by a standard 5-day pharmacokinetic TDM developmental testing model for antipsychotics, and a new model for characterizing variation in C/D by time course is therefore proposed. The time course of the accumulations identified suggests that both CYP inhibition and DNA regulatory mechanisms may be involved in the metabolism of these drugs. Long-term TDM can optimize treatment with risperidone and olanzapine and antipsychotics in general.
已有关于利培酮和奥氮平治疗药物监测（TDM）结果相互矛盾的报道。本研究旨在对一家封闭式专业护理机构中利培酮和奥氮平的长期药代动力学进行研究，该机构的药物管理由护理人员控制。
对一家封闭式专业护理机构中的67例难治性慢性精神分裂症患者进行利培酮和奥氮平的长期治疗方案中的TDM。在34例患者的利培酮组中进行了632次TDM，在33例患者的奥氮平组中进行了563次TDM。通过对剂量对数进行调整的分段线性混合模型回归分析血浆浓度随时间的对数。
我们发现利培酮血浆浓度/剂量比（C/D）在2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为增加了47%，且无明显平台期。
我们确定了利培酮和奥氮平药代动力学中的五个潜在干扰因素，这些因素可能导致药物不良反应。这些长期影响无法通过抗精神病药物的标准5天药代动力学TDM开发测试模型检测到，因此提出了一种通过时间进程表征C/D变化的新模型。所确定的累积时间进程表明，CYP抑制和DNA调节机制可能都参与了这些药物的代谢。长期TDM总体上可以优化利培酮、奥氮平和抗精神病药物的治疗。 （注：原文中“利培酮血浆浓度/剂量比（C/D）在2个月时（相对于基线浓度）累积峰值为2个月时（相对于基线浓度）累积峰值为……”表述重复且混乱，译文尽量按合理理解翻译，但原文此处可能有误）
