Oral olanzapine disposition in adolescents with schizophrenia or bipolar I disorder: a population pharmacokinetic model.
Oral olanzapine disposition in adolescents with schizophrenia or bipolar I disorder: a population pharmacokinetic model.
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DOI：
10.2165/11532580-000000000-00000
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Bergstrom, Richard F
中科院分区：
文献类型：
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作者：
Lobo, Evelyn D;Robertson-Plouch, Carol;Bergstrom, Richard F
背景：奥氮平是一种非典型抗精神病药，被批准用于治疗患有精神分裂症或 I 型双相情感障碍（躁狂或混合发作）的成人和青少年（13 -17 岁）。 目的：表征奥氮平在青少年中的药代动力学，估计变异性的来源，并确定显着的协变量。此外，将青少年奥氮平药代动力学参数与成人的药代动力学参数进行比较，以指导青少年患者的适当剂量建议。方法：进行了群体药代动力学模型研究。该模型的大部分药代动力学数据来自一项多中心、开放标签研究，其中总共 105 名年龄 13-17 岁（41.1-148 kg）、诊断为精神分裂症或 I 型双相情感障碍的患者口服奥氮平 2.5-20 mg，每日一次，为期 4.5 周。从每位患者处获取四份稳态血样。使用经过验证的高效液相色谱法和电化学检测法测定血浆中的奥氮平浓度。之前三项研究中 11 名青少年的类似数据也包括在内。开发了药代动力学模型，并使用非线性混合效应建模程序研究了患者特征（性别、体重、年龄、种族）的潜在影响。使用 Kolmogorov-Smirnov 2 样本检验，将青少年中奥氮平的药代动力学参数分布与先前报告的成人药代动力学参数分布（n = 912，精神分裂症诊断，奥氮平 5-20 mg/天）进行比较。使用蒙特卡罗模拟对外部验证数据集进行视觉预测检查。结果：通过单室药代动力学模型描述了青少年患者口服奥氮平的药代动力学。典型的模型估计口腔清除率 (CL/F) 为 13.6 L/h（70 kg 女性患者），口腔分布容积 (V/F) 为 899 L/h。患者间变异性（CL/F 为 40.5%，V/F 为 65.4%）和残差（27%）中等。体重和性别对 CL/F 有显着影响，体重较低的患者 CL/F 较低，男性比女性高约 30%。青少年的奥氮平暴露量通常比成人高 27%。大约 77% 的青少年和成人具有相当的 CL/F 值，69% 具有相当的 V/F 值。 结论：青少年患者口服奥氮平的药代动力学与成人相似，并且在 2.5-20 mg/天的剂量范围内呈线性。鉴于协变量效应的幅度较小以及患者间的变异性，青少年无需根据体重或性别进行剂量调整。
BACKGROUND: Olanzapine is an atypical antipsychotic approved for the treatment of adults and adolescents (aged 13 -17 years) with schizophrenia or bipolar I disorder (manic or mixed episodes).OBJECTIVES: To characterize the pharmacokinetics of olanzapine in adolescents, to estimate the sources of variability, and to identify significant co-variates. In addition, olanzapine pharmacokinetic parameters in adolescents were compared with those in adults to guide appropriate dosing recommendations for adolescent patients.METHODS: A population pharmacokinetic modeling study was performed. The majority of pharmacokinetic data for the model came from a multicenter, open-label study in which 4.5 weeks of oral olanzapine 2.5-20 mg once daily was administered to a total of 105 patients aged 13-17 years (41.1-148 kg) who had a diagnosis of schizophrenia or bipolar I disorder. Four blood samples at steady state were obtained from each patient. Olanzapine concentrations in plasma were determined using a validated high-performance liquid chromatography method with electrochemical detection. Similar data from 11 adolescents from three previous studies were also included. A pharmacokinetic model was developed and the potential effects of patient characteristics (sex, bodyweight, age, ethnic origin) were investigated using a nonlinear mixed effects modeling program. The distributions of pharmacokinetic parameters for olanzapine in adolescents were compared with those previously reported in adults (n = 912, diagnosis of schizophrenia, olanzapine 5-20 mg/day) using the Kolmogorov-Smirnov 2-sample test. A visual predictive check was performed using Monte Carlo simulations on an external validation dataset.RESULTS: The pharmacokinetics of oral olanzapine in adolescent patients were described by a one-compartment pharmacokinetic model. The typical model estimates were 13.6 L/h (70 kg female patient) for oral clearance (CL/F) and 899 L for oral volume of distribution (V/F). Interpatient variability (40.5% for CL/F, 65.4% for V/F) and residual error (27%) were moderate. Bodyweight and sex had a significant influence on CL/F, which was lower in patients with lower weights and approximately 30% higher in males than females. Olanzapine exposure was typically 27% higher in adolescents versus adults. Approximately 77% of adolescents and adults had comparable CL/F values and 69% had comparable V/F values.CONCLUSIONS: The pharmacokinetics of oral olanzapine in adolescent patients are similar to those in adults, and are linear in the dosage range of 2.5-20 mg/day. Given the small magnitude of co-variate effects and the interpatient variability, dose adjustments based on bodyweight or sex are not necessary in adolescents.