Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Community Psychiatry, FACT-team Heerhugowaard, Mental Health Organization North-Holland North, Heerhugowaard, The Netherlands.
J Clin Psychiatry. 2017 Nov/Dec;78(9):e1211-e1218. doi: 10.4088/JCP.16m11164.
Schizophrenia is a psychiatric disorder that affects approximately 0.4%-1% of the population worldwide. Diagnosis of schizophrenia is based primarily on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Clozapine is an antipsychotic drug that is mainly used in the treatment of schizophrenia patients who are refractory or intolerant to at least 2 other antipsychotics. Due to the high variability in pharmacokinetics of clozapine, therapeutic drug monitoring (TDM) is highly recommended for clozapine therapy.
To develop and clinically validate a novel sampling method using dried blood spot (DBS) to support TDM of clozapine and norclozapine.
From June 2014 to September 2014, 15 schizophrenia patients (18-55 years) treated with clozapine were included. Plasma, DBS samples made from venous samples (VDBS), and finger prick DBS (DBS) samples were obtained before administration and 2, 4, 6, and 8 hours after clozapine intake. The study was repeated in 6 Russian patients for external validation. Passing-Bablok regression and Bland-Altman analysis were used to compare the DBS, VDBS, and plasma results for clozapine and norclozapine.
The DBS validation results showed good linearity over the concentration time curve measured for clozapine and norclozapine. The accuracy and between- and within-day precision variation values were within accepted ranges. Different blood spot volumes and hematocrit values had no significant influence on the results. The DBS samples were stable at 20°C and 37°C for 2 weeks and at -20°C for 2 years. The mean clozapine and norclozapine DBS/plasma ratios were, respectively, 0.80 (95% CI, 0.76 to 0.85) and 1.063 (95% CI, 1.027 to 1.099) in Dutch patients. The mean clozapine DBS/DPS ratio in Russian patients was 0.70 (95% CI, 0.64 to 0.76).
DBS analysis is a reliable tool for blood sampling and performing TDM of clozapine and norclozapine in daily practice and substantially extends the opportunities for TDM of clozapine.
精神分裂症是一种影响全球约 0.4%-1%人口的精神疾病。精神分裂症的诊断主要基于《精神障碍诊断与统计手册》第五版（DSM-5）标准。氯氮平是一种抗精神病药物，主要用于治疗对至少 2 种其他抗精神病药物不耐受或无效的精神分裂症患者。由于氯氮平的药代动力学变异性很高，因此强烈建议进行治疗药物监测（TDM）。
开发并临床验证一种使用干血斑（DBS）进行采样的新方法，以支持氯氮平和去甲氯氮平的 TDM。
2014 年 6 月至 2014 年 9 月，纳入 15 名接受氯氮平治疗的精神分裂症患者（18-55 岁）。在给药前以及给药后 2、4、6 和 8 小时，采集静脉血样（VDBS）和指尖血样（DBS）制作的 DBS 样本。该研究在 6 名俄罗斯患者中进行了外部验证。采用 Passing-Bablok 回归和 Bland-Altman 分析比较了氯氮平和去甲氯氮平的 DBS、VDBS 和血浆结果。
氯氮平和去甲氯氮平的 DBS 验证结果表明，在整个浓度时间曲线范围内具有良好的线性关系。准确性和日内、日间精密度变化值均在可接受范围内。不同的血斑体积和血细胞比容值对结果没有显著影响。DBS 样本在 20°C 和 37°C 下可稳定保存 2 周，在-20°C 下可稳定保存 2 年。荷兰患者的氯氮平和去甲氯氮平 DBS/血浆比值分别为 0.80（95%置信区间，0.76-0.85）和 1.063（95%置信区间，1.027-1.099）。俄罗斯患者的氯氮平 DBS/DPS 比值平均为 0.70（95%置信区间，0.64-0.76）。
DBS 分析是一种可靠的血液采样工具，可用于氯氮平和去甲氯氮平的日常 TDM，并大大扩展了氯氮平 TDM 的机会。
