From the Department of Precision Medicine, Networked Services, Bessemer Wing, King's College Hospital NHS Foundation Trust, London, United Kingdom.
Biostatistics Group, Dean's Department, University of Otago, Wellington, Wellington, New Zealand.
J Clin Psychopharmacol. 2024;44(5):492-501. doi: 10.1097/JCP.0000000000001909. Epub 2024 Aug 22.
Smoking enhances plasma clozapine clearance, but the magnitude of the effect across the dose and age ranges is unclear.
We audited clozapine dose and predose plasma clozapine and N -desmethylclozapine (norclozapine) concentrations by sex and smoking habit in samples submitted for clozapine TDM, 1996-2017.
There were 105,316/60,792 and 34,288/31,309 samples from male/female smokers/nonsmokers, respectively. There were distinct dose-median plasma concentration trajectories for male/female smokers/nonsmokers across the range <50 to >850 mg d -1 . For both sexes, the percentage difference in median plasma clozapine in nonsmokers versus smokers averaged 50% but was greatest for men (76%) and women (59%) in the 151 to 250 mg d -1 dose band. In men, the percentage difference declined steadily to 34% at doses of ≥850 mg d -1 . In women, the difference after falling initially remained relatively constant at 40% to 54%. The pattern in median plasma clozapine/norclozapine ratio by plasma clozapine concentration and dose groups was independent of sex and smoking habit, but increased with plasma clozapine concentration (higher ratio at higher concentrations) and also changed with dose. Median plasma clozapine concentration and median clozapine dose by sex and smoking habit were similar up to age 60 years. Proportional weight gain was similar over time in smokers and nonsmokers of either sex.
These data explain the variations in the effect size of starting or stopping smoking on plasma clozapine concentration at constant dose reported in different studies. Changes in smoking habit in patients prescribed clozapine require prompt dose adjustment.
吸烟会增加氯氮平的血药清除率，但在不同剂量和年龄范围内，这种影响的程度尚不清楚。
我们对 1996 年至 2017 年间进行氯氮平治疗药物监测时提交的样本，按性别和吸烟习惯，审核了氯氮平剂量和氯氮平及 N-去甲基氯氮平（去甲氯氮平）的血药浓度。
男性吸烟者/非吸烟者/女性吸烟者/非吸烟者的样本分别为 105316/60792 例和 34288/31309 例。在氯氮平剂量<50 至>850mg/d 的范围内，男性/女性吸烟者/非吸烟者的血药浓度中位数-剂量曲线明显不同。对于两性，非吸烟者与吸烟者的血药氯氮平中位数的差异百分比平均为 50%，但在 151 至 250mg/d 剂量范围内，男性（76%）和女性（59%）最大。在男性中，这种差异百分比随着剂量的增加而逐渐下降至 850mg/d 以上时稳定在 34%。在女性中，差异百分比在初始下降后基本保持在 40%至 54%。在不同氯氮平浓度和剂量组，氯氮平/去甲氯氮平中位数比值的模式独立于性别和吸烟习惯，但随着氯氮平浓度的增加而增加（浓度越高比值越高），并且也随剂量而变化。在男女中，在 60 岁之前，按性别和吸烟习惯的氯氮平血药浓度和剂量中位数相似。在男女吸烟者和非吸烟者中，随着时间的推移，体重的比例增加相似。
这些数据解释了不同研究中报道的，在剂量不变时开始或停止吸烟对氯氮平血药浓度影响程度的差异。氯氮平处方患者的吸烟习惯改变需要及时调整剂量。
