Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years
Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years
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DOI：
10.1007/s00280-013-2069-1
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发表时间：
2013-03-01
影响因子：
3
通讯作者：
Hempel, Georg
中科院分区：
文献类型：
--
作者：
Kontny, Nina E.;Wuerthwein, Gudrun;Hempel, Georg
本研究的目的是建立阿霉素和阿霉素的群体药代动力学模型，该模型可以为成人和3岁以上儿童阿霉素的药物动力学参数清除量、中央室分布体积、阿霉素清除量和代谢物室分布体积提供更好的估计值。为了进一步研究协变量体表面积、体重、身高、年龄、体重指数、性别和瘦体重对药代动力学参数的潜在影响，将三个不同的数据集合并，其中两个包含成人数据，一个包含成人和儿童数据，并对合并后的数据集进行回顾分析。总体而言，合并数据集包含82名患者[成人和18名儿童(<；18岁)]的934个阿霉素和935个阿霉素血浆浓度。利用这一组合数据集，使用NONMEMA(R)7.2和预定义的建模策略开发了一个群体药代动力学模型。检验了不同的结构模型、误差模型和估计方法，并检验了个体间和场合间的变异性(单独(两次或三次)阿霉素输注之间的变异性)。使用52名患者的子集，研究了不同协变量对药代动力学参数的影响。根据最佳模型得到的阿霉素浓度的药代动力学参数估计值是固定的，并且在模型中增加了一个额外的阿霉素隔室。使用最终的两种物质的模型，评估了阿霉素和阿霉素清除的潜在年龄依赖性和体重指数依赖性，以及中央和代谢物隔室的分布体积。一个四室模型最好地描述了组合数据集的阿霉素和阿霉素数据。该模型包括阿霉素清除量、外周隔室间清除量、阿霉素清除量以及中央、外周和代谢物隔室分布体积的比例残差模型和个体间变异性。此外，体表面积作为所有药代动力学参数的协变量，以及阿霉素清除量和中央隔室分布体积的时间间变异性被纳入模型中。对于体表面积为1.8 mA(2)的患者，阿霉素清除量为53.3 L/h(个体间变异31%，时机间变异13%)，中央隔室分布体积为17.7 L(个体间变异19%，时机变异21%)。模型对阿霉素的残差为22%，对阿霉素的残差为26%。阿霉素的清除量估计为44 L/小时(个体变异50%)，代谢物室的分布体积为1,150 L(个体变异57%)。对可能的年龄依赖性和体重指数依赖性的评估显示，在年轻患者中，中央隔室的分布体积较小(归一化为身体表面积)，代谢物隔室的分布体积较大(归一化为体重)。阿霉素和阿霉素的四室NONMEMA(R)模型充分描述了成人和儿童(3岁)的血浆浓度。未发现年龄对阿霉素或阿霉素清除的显著影响，该分析不支持修改目前用于儿童和成人的给药策略。
The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (< 18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEMA (R) 7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 mA(2), the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.A four-compartment NONMEMA (R) model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (> 3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.