Department I of Internal Medicine, University of Cologne, Cologne, Germany.
Eur J Clin Pharmacol. 2012 Jun;68(6):987-95. doi: 10.1007/s00228-012-1212-y.
To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting.
Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity.
A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8–60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution).
We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.
评估在接受化疗的急性髓细胞白血病（AML）或骨髓增生异常综合征（MDS）患者中泊沙康唑的药代动力学（PK）特性。
采用高效液相色谱法测定 AML/MDS 患者接受预防性泊沙康唑治疗时的泊沙康唑浓度。采用非线性混合效应模型建立群体 PK 模型。测试的协变量列表包括年龄、体重、身高、性别、泊沙康唑剂量、种族、抗肿瘤化疗联合用药、雷尼替丁或泮托拉唑、合并发热、腹泻、白细胞计数和γ-谷氨酰转移酶血浆活性。
共获得 84 例患者的 643 个泊沙康唑血清浓度。以一室模型加一级吸收和消除作为基本结构模型，数据拟合良好，表观清除率为 56.8 L/h（95%置信区间[CI]：52.860.8 L/h），表观分布容积为 2130 L（95%CI：16462614 L）。腹泻的存在和质子泵抑制剂（PPI）的联合用药对表观清除率（CL/F）有显著影响（CL/F 分别增加 1.5 倍和 1.6 倍），体重（每公斤表观分布容积增加 33.4 L）和化疗联合用药（表观分布容积降低 0.6 倍）。
我们建立了 AML/MDS 患者平均泊沙康唑浓度的预测基础。患者体重、腹泻的存在以及伴随的药物治疗（化疗和泮托拉唑）对泊沙康唑的暴露有显著影响。在获得治疗药物监测结果之前，根据腹泻的存在以及化疗或质子泵抑制剂联合用药时，调整起始剂量是合理的。有必要进一步研究不同化疗方案与泊沙康唑之间的相互作用。
