NONLINEAR PHARMACOKINETICS AND METABOLISM OF PACLITAXEL AND ITS PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIPS IN HUMANS
NONLINEAR PHARMACOKINETICS AND METABOLISM OF PACLITAXEL AND ITS PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIPS IN HUMANS
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DOI：
10.1200/jco.1995.13.1.180
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发表时间：
1995-01-01
影响因子：
45.3
通讯作者：
EGORIN, MJ
中科院分区：
文献类型：
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作者：
GIANNI, L;KEARNS, CM;EGORIN, MJ
目的：为了表征和建模紫杉醇在人体中的处置和定义紫杉醇处置和其毒性和efficacy.Patients和方法之间的药效学关系：紫杉醇的药代动力学进行了研究，在55个疗程的治疗30例。晚期卵巢癌患者（n = 15）接受135 mg/m2或175 mg/m2的紫杉醇3小时或24小时输注，晚期乳腺癌患者（n = 15）接受225 mg/m2的紫杉醇3小时输注。通过高效液相色谱法（HPLC）定量紫杉醇和6 α-羟基紫杉醇。通过非房室模型和模型依赖性方法评估药代动力学。统计学和回归models.Results：紫杉醇的处置是非线性的人类，在3小时的时间表，6 α-羟基紫杉醇被确定在所有患者的血浆中治疗。紫杉醇和6 α-羟基紫杉醇的血浆处置可以通过具有多个非线性过程的模型很好地描述。中性粒细胞与紫杉醇或6 α-羟基紫杉醇的曲线下面积（AUC）或帕利他赛峰浓度（C-max）无关。结论：紫杉醇在人体内的分布是非线性的，紫杉醇代谢为6 α-羟基紫杉醇可能是一个重要的解毒途径。骨髓抑制与血浆紫杉醇浓度大于或等于0.05 μ mol/L的持续时间有关。紫杉醇的新剂量和时间表的试验应考虑其非线性分布，以排除不良临床后果，特别是如果药物通过短时间输注给药。我们的药代动力学模型应被证明是一个强大的工具，在预测紫杉醇处置，无论剂量和时间表，并应促进进一步的药效学研究。(C)1995年，美国临床肿瘤学会。
Purpose: To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy.Patients and Methods: Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel wets administered at 135 mg/m(2) or 175 mg/m(2) by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m(2) by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models.Results: Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multi-ple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (C-max). Neutropenia was related to the duration that plasma concentrations were greater than or equal to 0.05 mu mol/L, a relationship that is well described by a sigmoid maximum response (E(max)) model.Conclusion: The disposition of paclitaxel in humans is nonlinear, Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are greater than or equal to 0.05 mu mol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.(C) 1995 by American Society of Clinical Oncology.