Factors Influencing Pharmacokinetics of Prophylactic Posaconazole in Patients Undergoing Allogeneic Stem Cell Transplantation
Factors Influencing Pharmacokinetics of Prophylactic Posaconazole in Patients Undergoing Allogeneic Stem Cell Transplantation
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DOI：
10.1128/aac.01027-09
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发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Rueping, M. J. G. T.
中科院分区：
文献类型：
--
作者：
Kohl, V.;Mueller, C.;Rueping, M. J. G. T.
本研究的目的是阐明影响异基因造血干细胞移植（SCT）受者口服泊沙康唑药代动力学的因素。在2007年5月至2008年11月期间，从科隆大学医院接受治疗药物监测（TDM）的所有SCT接受者中获得了血清预防性泊沙康唑浓度的临床数据。泊沙康唑浓度测定采用高效液相色谱法。我们使用非线性混合效应模型（NONMEM）开发了群体药代动力学模型。检测的协变量列表包括年龄、体重、身高、性别、泊沙康唑剂量、人种、联合化疗、干细胞移植日、雷尼替丁、泮托拉唑、环孢素或他克莫司联合给药、并发发热、腹泻和血浆γ-谷氨酰转移酶活性。共获得32例患者的149个血清泊沙康唑浓度。以一级吸收和消除作为基本结构模型的一室模型适当描述了数据，表观清除率为75.8 L/h（95%置信区间[CI]，65.2 - 86.4 L/h），表观体积分布为835 L（95% CI，559 - 1，111 L）。在检测的协变量中，发现年龄（分布容积减少123升/岁）和腹泻（生物利用度损失59%）具有显著影响。提供了一个基础预测的平均泊沙康唑浓度在异基因造血干细胞移植受者与血液系统恶性肿瘤的给定剂量。在获得TDM结果之前，根据腹泻和年龄对起始剂量进行相应调整似乎是合理的。
The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.