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首页> 外文期刊>Clinical drug investigation >Long-Term Therapeutic Drug Monitoring of Risperidone and Olanzapine Identifies Altered Steady-State PharmacokineticsA Clinical, Two-Group, Naturalistic Study
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Long-Term Therapeutic Drug Monitoring of Risperidone and Olanzapine Identifies Altered Steady-State PharmacokineticsA Clinical, Two-Group, Naturalistic Study

机译：利培酮和奥氮平的长期治疗药物监测可确定稳态药物代谢动力学的改变临床，两组自然研究

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Background and objective: 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.Methods: 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.Results: 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. Conclusion: 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 pharmacokine-tic 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.
机译：背景与目的：已报告了利培酮和奥氮平的治疗药物监测（TDM）结果冲突。这项研究着手在锁定的专业护理机构中检查利培酮和奥氮平的长期药代动力学，该设施由护理人员控制药物的使用。方法：TDM在利培酮和奥氮平的长期治疗方案中治疗67例难治性慢性精神分裂症患者，应在锁定的熟练护理设施中。利培酮组34例患者进行632次TDM，奥氮平组33例患者进行563次。通过调整剂量对数的分段线性混合模型回归分析随时间变化的血浆浓度对数。结果：我们发现2个月时利培酮的血浆浓度/剂量比（C / D）累积峰值为49％（相对于基线浓度）以及6个月时2个月水平的9-羟基-利培酮和总C / D积累峰分别达到66％和55％，这与我们先前的研究（包括一部分数据点）进行了比较这里。细胞色素P450（CYP）2D6将利培酮转化为9-羟基-利培酮提示在最初的2个月内抑制CYP2D6或DNA下调。奥氮平在4个月时显示C / D积累峰值，比基线高31％，而在18个月时缓慢上升至基线以上47％，没有明显的平台期。结论：我们确定了利培酮和奥氮平在药代动力学中的五个潜在扰动，它们可能导致药物不良反应。这些长期作用不会被抗精神病药的标准5天药代动力学TDM开发测试模型捕获，因此提出了一种表征C / D随时间变化的新模型。鉴定出的积累的时间过程表明，CYP抑制和DNA调节机制都可能与这些药物的代谢有关。

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