Pérez-Blanco Jonás Samuel, Santos-Buelga Dolores, Fernández de Gatta María Del Mar, Hernández-Rivas Jesús María, Martín Alejandro, García María José
Department of Pharmaceutical Sciences - Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain.
Salamanca Institute for Biomedical Research (IBSAL), Salamanca, Spain.
Br J Clin Pharmacol. 2016 Dec;82(6):1517-1527. doi: 10.1111/bcp.13070. Epub 2016 Sep 6.
The aims of the study were: (i) to characterize the pharmacokinetics (PK) of doxorubicin (DOX) and doxorubicinol (DOXol) in patients diagnosed with non-Hodgkin's lymphoma (NHL) using a population approach; (ii) to evaluate the influence of various covariates on the PK of DOX; and (iii) to evaluate the role of DOX and DOXol exposure in haematological toxicity.
Population PK modelling (using NONMEM) was performed using DOX and DOXol plasma concentration-time data from 45 NHL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). The influence of drug exposure on haematological toxicity was analysed using the Mann-Whitney-Wilcoxon test.
A five-compartment model, three for DOX and two for DOXol, with first-order distribution and elimination for both entities best described the data. Population estimates for parent drug (CL) and metabolite (CL ) clearance were 62 l h and 27 l h , respectively. The fraction metabolized to DOXol (F ) was estimated at 0.22. While bilirubin and aspartate aminotransferase showed an influence on the CL and CL , the objective function value decrease was not statistically significant. A trend towards an association between the total area under the concentration-time curve (AUC ), the area under the concentration-time curve for DOX (AUC) plus the area under the concentration-time curve for DOXol (AUC ), and the neutropenia grade (P = 0.068) and the neutrophil counts (P = 0.089) was observed, according to an exponential relationship.
The PK of DOX and DOXol were well characterized by the model developed, which could be used as a helpful tool to optimize the dosage of this drug. The results suggest that the main active metabolite of DOX, DOXol, is involved in the haematological toxicity of the parent drug.
本研究的目的是：（i）采用群体方法描述多柔比星（DOX）和多柔比星醇（DOXol）在非霍奇金淋巴瘤（NHL）患者中的药代动力学（PK）特征；（ii）评估各种协变量对DOX药代动力学的影响；（iii）评估DOX和DOXol暴露在血液学毒性中的作用。
使用来自45例接受R-CHOP（利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松）治疗的NHL患者的DOX和DOXol血浆浓度-时间数据进行群体PK建模（使用NONMEM）。使用曼-惠特尼-威尔科克森检验分析药物暴露对血液学毒性的影响。
一个五室模型，其中三室用于DOX，两室用于DOXol，两者均具有一级分布和消除，能最好地描述数据。母体药物（CL）和代谢物（CL）清除率的群体估计值分别为62 l/h和27 l/h。代谢为DOXol的分数（F）估计为0.22。虽然胆红素和天冬氨酸转氨酶对CL和CL有影响，但目标函数值的降低无统计学意义。根据指数关系，观察到浓度-时间曲线下总面积（AUC）、DOX的浓度-时间曲线下面积（AUC）加上DOXol的浓度-时间曲线下面积（AUC）与中性粒细胞减少分级（P = 0.068）和中性粒细胞计数（P = 0.089）之间存在关联趋势。
所建立的模型很好地描述了DOX和DOXol的药代动力学特征，可作为优化该药物剂量的有用工具。结果表明，DOX的主要活性代谢物DOXol参与了母体药物的血液学毒性。
