Bigos Kristin L, Pollock Bruce G, Coley Kim C, Miller Del D, Marder Stephen R, Aravagiri Manickam, Kirshner Margaret A, Schneider Lon S, Bies Robert R
Department of Pharmaceutical Sciences, University of Pittsburgh, School of Pharmacy, 805 Salk Hall, 3501 Terrace St, Pittsburgh, PA 15261, USA.
J Clin Pharmacol. 2008 Feb;48(2):157-65. doi: 10.1177/0091270007310385.
Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.
抗精神病药物的反应差异很大，这可能部分归因于药物暴露的不同。本研究的目的是评估奥氮平浓度暴露的程度和变异性。作为临床抗精神病药物干预有效性试验（CATIE）的一部分，阿尔茨海默病患者（n = 117）和精神分裂症患者（n = 406）接受了奥氮平治疗。这些患者（n = 523）共提供了1527份血浆样本用于测定奥氮平浓度。采用非线性混合效应模型确定奥氮平的群体药代动力学，并评估患者特异性协变量作为药物暴露变异性的潜在影响因素。奥氮平的群体平均清除率和分布容积分别为16.1 L/h和2150 L。奥氮平的清除率变化近10倍（范围为6.66 - 67.96 L/h）。吸烟状况、性别和种族分别解释了26%、12%和7%的变异性（P <.0001）。吸烟者清除奥氮平的速度比非吸烟者/既往吸烟者快55%（P <.0001）。男性清除奥氮平的速度比女性快38%（P <.0001）。自我认定为黑人或非裔美国人的患者清除奥氮平的速度比其他种族快26%（P <.0001）。奥氮平暴露在性别、种族和吸烟方面的差异可能是奥氮平反应变异性的部分原因。
