Diaz F J, Santoro V, Spina E, Cogollo M, Rivera T E, Botts S, de Leon J
Department of Statistics, Universidad Nacional, Medellin, Colombia.
Pharmacopsychiatry. 2008 May;41(3):81-91. doi: 10.1055/s-2007-1004591.
The purpose of this study was to estimate the effect sizes of drug interactions on plasma clozapine concentrations, adjusting for potentially confounding factors such as smoking.
The estimation was performed by using a mixed model, and a combination of unpublished (N=83) and published (N=172) data that included patients taking phenobarbital, valproic acid, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram and reboxetine, and patients not taking co-medications.
The 255 patients provided a total of 415 steady-state trough plasma clozapine concentrations. Each patient provided 1 to 15 measures of plasma clozapine concentrations. Total plasma clozapine concentration, defined as the sum of plasma clozapine and norclozapine concentrations, was also investigated. A random intercept linear model of the natural log of plasma clozapine concentration with the natural log of dose and other variables as independent variables was built. The model confirmed that phenobarbital induces clozapine metabolism (effect size, E=-28%), and that fluoxetine (E=+42%), fluvoxamine (E=+263%) and paroxetine (E=+30%) inhibit it. Valproic acid appeared to inhibit clozapine metabolism in non-smokers (effect size, E=+16%), whereas it appeared to induce clozapine metabolism in smokers (E=-22%). The effect sizes of smoking on plasma clozapine concentration were -20% in patients not taking valproic acid, and -46% in patients taking valproic acid. Thus, smoking induces clozapine metabolism, and this induction may be stronger when the patient is taking valproic acid. The effect sizes allowed the computation of clozapine dose-correction factors for phenobarbital, 1.4 [95% confidence interval, CI, (1.1, 1.7)]; paroxetine, 0.77 (0.67, 0.89); fluoxetine, 0.70 (0.64, 0.78); fluvoxamine, 0.28 (0.22, 0.35); and valproic acid [0.86 (0.75, 1.0) in non-smokers, and 1.3 (0.96, 1.73) in smokers]. Sertraline, reboxetine and citalopram had no obvious effects.
The results for total plasma clozapine concentrations are similar to those for plasma clozapine concentrations. The main limitations of this study were that the computed effect sizes reflect only the doses and treatment-durations of the co-medications studied, and that the substantial "noise" of the clinical environment may make it difficult to detect the effects of some variables, particularly those with small effect sizes. Gender was not significant probably due to its relatively small effect size in the studied population, and age was not significant probably due to the limited age variability.
This article contributes to the clozapine literature by describing a possible interaction between taking valproic acid and smoking, which modifies plasma clozapine concentrations, by estimating the effect sizes of other compounds on plasma clozapine concentrations after correcting for confounders, and by providing dose-correction factors for clinicians.
本研究旨在评估药物相互作用对血浆氯氮平浓度的效应大小，并对吸烟等潜在混杂因素进行校正。
采用混合模型进行评估，纳入未发表数据（N = 83）和已发表数据（N = 172），数据涉及服用苯巴比妥、丙戊酸、氟伏沙明、氟西汀、帕罗西汀、舍曲林、西酞普兰和瑞波西汀的患者以及未服用联合用药的患者。
255例患者共提供了415个稳态谷浓度血浆氯氮平测量值。每位患者提供1至15个血浆氯氮平浓度测量值。还对总血浆氯氮平浓度（定义为血浆氯氮平和去甲氯氮平浓度之和）进行了研究。建立了以血浆氯氮平浓度自然对数为因变量、剂量自然对数及其他变量为自变量的随机截距线性模型。该模型证实，苯巴比妥诱导氯氮平代谢（效应大小，E = -28%），氟西汀（E = +42%）、氟伏沙明（E = +263%）和帕罗西汀（E = +30%）抑制氯氮平代谢。丙戊酸在非吸烟者中似乎抑制氯氮平代谢（效应大小，E = +16%），而在吸烟者中似乎诱导氯氮平代谢（E = -22%）。吸烟对未服用丙戊酸患者血浆氯氮平浓度的效应大小为 -20%，对服用丙戊酸患者为 -46%。因此，吸烟诱导氯氮平代谢，且当患者服用丙戊酸时这种诱导作用可能更强。效应大小可用于计算苯巴比妥的氯氮平剂量校正因子为1.4 [95%置信区间，CI，(1.1, 1.7)]；帕罗西汀为0.77 (0.67, 0.89)；氟西汀为0.70 (0.64, 0.78)；氟伏沙明为0.28 (0.22, 0.35)；丙戊酸在非吸烟者中为[0.86 (0.75, 1.0)]，在吸烟者中为1.3 (0.96, 1.73)。舍曲林、瑞波西汀和西酞普兰无明显作用。
总血浆氯氮平浓度的结果与血浆氯氮平浓度的结果相似。本研究的主要局限性在于，计算出的效应大小仅反映所研究联合用药的剂量和治疗持续时间，且临床环境中的大量“噪声”可能使检测某些变量的效应变得困难，尤其是那些效应大小较小的变量。性别可能因在所研究人群中效应大小相对较小而无显著意义，年龄可能因年龄变异性有限而无显著意义。
本文通过描述服用丙戊酸与吸烟之间可能存在的相互作用（该相互作用会改变血浆氯氮平浓度）、在校正混杂因素后估计其他化合物对血浆氯氮平浓度的效应大小以及为临床医生提供剂量校正因子，对氯氮平相关文献做出了贡献。
