Patteet Lisbeth, Maudens Kristof E, Vermeulen Zarha, Dockx Greetje, De Doncker Mireille, Morrens Manuel, Sabbe Bernard, Neels Hugo
Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Clin Biochem. 2014 Dec;47(18):336-9. doi: 10.1016/j.clinbiochem.2014.09.021. Epub 2014 Oct 5.
Clozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP-TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography-tandem mass spectrometric method (UHPLC-MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples.
Serum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid-liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC-MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP-TDM guidelines.
For clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350-600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100-600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range.
This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.
氯氮平是一种非典型抗精神病药物，治疗窗窄且有严重的毒副作用。根据AGNP-TDM共识指南，强烈推荐对氯氮平和其代谢产物去甲氯氮平进行治疗药物监测（TDM）。将330份送往安特卫普医院网络毒理学实验室进行氯氮平监测的血清样本，采用一种新的超高效液相色谱-串联质谱法（UHPLC-MS/MS）进行检测。本研究的目的是评估该方法用于氯氮平和去甲氯氮平的TDM，同时确定这些血清样本中存在的其他抗精神病药物。
在早晨服用抗精神病药物前采集血清样本（谷浓度）。所有样本经甲基叔丁基醚简单液液萃取后，采用经过充分验证的UHPLC-MS/MS方法进行分析，该方法能够定量16种不同的抗精神病药物及其8种主要代谢产物。将血清浓度与AGNP-TDM指南定义的治疗范围进行比较。
对于氯氮平，只有22.3%的血清浓度在350 - 600 ng/mL的治疗范围内，而67.9%的浓度低于350 ng/mL。对于去甲氯氮平，68.2%的血清样本在100 - 600 ng/mL的治疗范围内。氯氮平与去甲氯氮平的平均比值为1.7（标准差0.8）。330份血清样本中有218份含有除氯氮平之外的其他抗精神病药物。这些浓度中只有52.5%在建议范围内。
这项回顾性研究强调了氯氮平和其他抗精神病药物TDM的重要性，因为许多患者的血清浓度未达最佳水平。
