乳腺癌患者多柔比星输注后急性N末端B型利钠肽原的药代动力学-药效学建模
Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer.
作者信息
Liang Shuang, Brundage Richard C, Jacobson Pamala A, Blaes Anne, Kirstein Mark N
机构信息
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
Division of Hematology/Oncology/Transplantation, University of Minnesota, Minneapolis, MN, 55455, USA.
出版信息
Br J Clin Pharmacol. 2016 Sep;82(3):773-83. doi: 10.1111/bcp.12989. Epub 2016 Jun 3.
AIMS
The aim of the present study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment.
METHODS
The study enrolled 17 female patients with stages 1-3 breast cancer and receiving adjuvant doxorubicin (60 mg m(-2) ) and cyclophosphamide (600 mg m(-2) ) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP.
RESULTS
A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8-73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability.
CONCLUSION
The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.
目的
本研究旨在建立一个药代动力学-药效学（PK-PD）模型，以描述阿霉素治疗48小时内血浆阿霉素浓度与N末端B型利钠肽原（NT-proBNP）浓度之间的关系。
方法
本研究纳入了17例1-3期乳腺癌女性患者，她们每14天接受一次阿霉素（60 mg m(-2)）和环磷酰胺（600 mg m(-2)）辅助治疗，共四个周期。在连续两个周期中，在输注前以及阿霉素输注结束后长达48小时收集血浆阿霉素、阿霉素醇、肌钙蛋白和NT-proBNP的浓度。采用非线性混合效应模型来描述阿霉素和NT-proBNP的PK-PD关系。
结果
一个三室母体药物和一室代谢物模型能最好地描述阿霉素和阿霉素醇的药代动力学。肌钙蛋白浓度与基线保持相似。一个带有转运室的间接药效学模型能最好地描述阿霉素暴露与急性NT-proBNP反应之间的关系。估计的药效学参数存在较大的个体间变异性（总分析变异性为38.8-73.9%）。未观察到包括使用依那普利在内的患者临床因素与阿霉素药代动力学或NT-proBNP药效学变异性有显著关联。
结论
通过群体PK-PD模型成功描述了阿霉素浓度与急性NT-proBNP反应之间的关系。该模型将为未来研究确定与阿霉素急性反应相关的临床因素提供有价值的框架。未来有必要研究这种急性反应与随后心力衰竭之间的关系。如果建立了这种关系，该模型可以提供有关患者对阿霉素诱导的长期心脏毒性易感性的有用信息。
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