Ansermot Nicolas, Vathanarasa Harish, Ranjbar Setareh, Gholam Mehdi, Crettol Séverine, Vandenberghe Frederik, Gamma Franziska, Plessen Kerstin Jessica, von Gunten Armin, Conus Philippe, Eap Chin B
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
Psychiatric Epidemiology and Psychopathology Research Centre, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
Ther Drug Monit. 2024 Jun 3;46(6):828-36. doi: 10.1097/FTD.0000000000001227.
Therapeutic drug monitoring (TDM) is strongly recommended for olanzapine due to its high pharmacokinetic variability. This study aimed to investigate the impact of various clinical factors on olanzapine plasma concentrations in patients with psychiatric disorders.
The study used TDM data from the PsyMetab cohort, including 547 daily dose-normalized, steady-state, olanzapine plasma concentrations (C:D ratios) from 248 patients. Both intrinsic factors (eg, sex, age, body weight) and extrinsic factors (eg, smoking status, comedications, hospitalization) were examined. Univariate and multivariable, linear, mixed-effects models were employed, with a stepwise selection procedure based on Akaike information criterion to identify the relevant covariates.
In the multivariable model (based on 440 observations with a complete data set), several significant findings emerged. Olanzapine C:D ratios were significantly lower in smokers (β = -0.65, P < 0.001), valproate users (β = -0.53, P = 0.002), and inpatients (β = -0.20, P = 0.025). Furthermore, the C:D ratios decreased significantly as the time since the last dose increased (β = -0.040, P < 0.001). The male sex had a significant main effect on olanzapine C:D ratios (β = -2.80, P < 0.001), with significant interactions with age (β = 0.025, P < 0.001) and body weight (β = 0.017, P = 0.011). The selected covariates explained 30.3% of the variation in C:D ratios, with smoking status accounting for 7.7% and sex contributing 6.9%. The overall variation explained by both the fixed and random parts of the model was 67.4%. The model facilitated the prediction of olanzapine C:D ratios based on sex, age, and body weight.
The clinical factors examined in this study, including sex, age, body weight, smoking status, and valproate comedication, remarkably influence olanzapine C:D ratios. Considering these factors, in addition to TDM and the clinical situation, could be important for dose adjustment.
由于奥氮平具有较高的药代动力学变异性，强烈推荐进行治疗药物监测（TDM）。本研究旨在调查各种临床因素对精神障碍患者奥氮平血药浓度的影响。
该研究使用了来自PsyMetab队列的TDM数据，包括248例患者的547个每日剂量标准化、稳态的奥氮平血药浓度（C:D比值）。研究考察了内在因素（如性别、年龄、体重）和外在因素（如吸烟状况、合并用药、住院情况）。采用单变量和多变量线性混合效应模型，并基于赤池信息准则进行逐步选择程序以识别相关协变量。
在多变量模型（基于440个完整数据集的观察结果）中，出现了几个重要发现。吸烟者（β = -0.65，P < 0.001）、丙戊酸盐使用者（β = -0.53，P = 0.002）和住院患者（β = -0.20，P = 0.025）的奥氮平C:D比值显著较低。此外，自上次给药以来的时间增加时，C:D比值显著降低（β = -0.040，P < 0.001）。男性性别对奥氮平C:D比值有显著的主效应（β = -2.80，P < 0.001），与年龄（β = 0.025，P < 0.001）和体重（β = 0.017，P = 0.011）有显著交互作用。所选协变量解释了C:D比值变异的30.3%，吸烟状况占7.7%，性别占6.9%。模型的固定部分和随机部分共同解释的总变异为67.4%。该模型有助于根据性别、年龄和体重预测奥氮平C:D比值。
本研究中考察的临床因素，包括性别、年龄、体重、吸烟状况和丙戊酸盐合并用药，对奥氮平C:D比值有显著影响。除了TDM和临床情况外，考虑这些因素对于剂量调整可能很重要。
