Association of clozapine and norclozapine levels with patient and therapy characteristics—focus on interaction with valproic acid,European Journal of Clinical Pharmacology

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Association of clozapine and norclozapine levels with patient and therapy characteristics—focus on interaction with valproic acid
European Journal of Clinical Pharmacology ( IF 2.4 ) Pub Date : 2023-09-21 , DOI: 10.1007/s00228-023-03569-2
Bojana Panić ₁ , Marija Jovanović ₁ , Vera Lukić ₂ , Katarina Vučićević ₁ , Branislava Miljković ₁ , Srđan Milovanović _{3,

4}

Affiliation

Purpose

The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use.

Methods

This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients’ data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ.

Results

A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability.

Conclusion

The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant.

中文翻译：

氯氮平和去甲氯氮平水平与患者和治疗特征的关联——重点关注与丙戊酸的相互作用

目的

该研究的目的是检查氯氮平 (CLZ) 和去甲氯氮平 (NCLZ) 治疗药物监测 (TDM) 数据以及药代动力学变异的相关来源，特别是丙戊酸 (VPA) 使用的影响。

方法

这项研究纳入了 126 名接受 CLZ 单一或联合治疗的精神疾病患者。从临床记录中回顾性收集常规 TDM 期间患者的数据。使用IBM SPSS统计软件（版本22，纽约，美国）计算描述性和统计分析。基于最后的观察，使用多元线性回归来评估人口特征、生活习惯和联合治疗与 CLZ 和 NCLZ 以及 CLZ/NCLZ 的剂量校正血清水平 (C/D) 之间的相关性。

结果

共测定了 126 名患者的 295 个 CLZ 浓度，平均值为 275.5 ± 174.4 µg/L，同时测定了 74 名患者的 124 个 NCLZ 浓度，平均值为 194.6 ± 149.8 µg/L。性别和吸烟对ln转化的 CLZ C/D 具有统计学上显着的影响，而性别、吸烟和 VPA 治疗与ln转化的 NCLZ C/D相关。根据最终模型，接受 VPA 的患者的 NCLZ C/D 值预计较低，约为 45.9%。同时使用 VPA 是唯一检测到导致 CLZ/NCLZ 变异的因素。