Background

Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment.

Objective

We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service.

Methods

Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005–2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included.

Results

In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032).

Conclusions

The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

中文翻译：

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转换与维持​​治疗患者中氯氮平的绝对和剂量调整血清浓度：1979 名患者的观察性研究

背景

氯氮平是治疗精神分裂症的有效药物，对其他药物没有反应，但一些患者出现不足或不良反应并停止治疗。

客观的

我们调查了氯氮平血清浓度与从治疗药物监测服务的大量真实世界患者中改用其他抗精神病药物之间的潜在关联。

方法

在 2005-2019 年期间，对 1979 名挪威患者进行了 100 至 1000 毫克/天给药期间氯氮平的绝对和剂量调整后的血清浓度（浓度与剂量比 [C/D 比]）。使用线性混合模型比较了改用其他抗精神病药物与维持氯氮平治疗的患者的这些变量。49% 的患者有吸烟习惯。为防止潜在的不依从性影响氯氮平转换，仅纳入血清浓度高于参考下限范围 50% 的患者。

结果

在研究期间，总共有 190 名患者（9.6%）从氯氮平转用另一种抗精神病药物，而其余患者未被检测为转换者，并被解释为维持治疗。转换治疗的患者的氯氮平绝对浓度（954 对 1245 nmol/L；p < 0.001）和每日剂量（305 对 362 mg/天；p < 0.001）比未转换的患者低 23.5%，使氯氮平校正吸烟习惯后，转换者的 C/D 比比非转换者低 9.7%（2.80 与 3.10 nmol/L/mg/天；p = 0.032）。

结论

本研究表明，氯氮平绝对和剂量调整后的血清浓度降低与氯氮平停药有关。无论转换者与非转换者的处方剂量如何，氯氮平浓度显着降低可能表明存在氯氮平停药风险的药代动力学机制。