Choi Soo An, Yun Hwi-yeol, Lee Eun Sook, Shin Wan Gyoon
Department of Pharmacy, Seoul National University Bundang Hospital, Seoul, South Korea.
College of Pharmacy, Chungnam National University, Daejeon, South Korea.
Clin Ther. 2014 Mar 1;36(3):389-400. doi: 10.1016/j.clinthera.2014.01.019. Epub 2014 Mar 5.
Safe and effective use of digoxin in hospitalized populations requires information about the drug's pharmacokinetics and the influence of various factors on drug disposition. However, no attempts have been made to link an individual's digoxin requirements with nutritional status.
The main goal of this study was to estimate the population pharmacokinetics of digoxin and to identify the nutritional status that explains pharmacokinetic variability in hospitalized Korean patients.
Routine therapeutic drug-monitoring data from 106 patients who received oral digoxin at Seoul National University Bundang Hospital were retrospectively collected. The pharmacokinetics of digoxin were analyzed with a 1-compartment, open-label pharmacokinetic model by using a nonlinear mixed-effects modeling tool (NONMEM) and a multiple trough screening approach.
The effect of demographic characteristics and biochemical and nutritional indices were explored. Estimates generated by using NONMEM indicated that the CL/F of digoxin was influenced by renal function, serum potassium, age, and percentage of ideal body weight (PIBW). These influences could be modeled by following the equation CL/F (L/h) = 1.36 × (creatinine clearance/50)(1.580) × K(0.835) × 0.055 × (age/65) × (PIBW/100)(0.403). The interindividual %CV for CL/F was 34.3%, and the residual variability (SD) between observed and predicted concentrations was 0.225 μg/L. The median estimates from a bootstrap procedure were comparable and within 5% of the estimates from NONMEM. Correlation analysis with the validation group showed a linear correlation between observed and predicted values.
The use of this model in routine therapeutic drug monitoring requires that certain conditions be met which are consistent with the conditions of the subpopulations in the present study. Therefore, further studies are needed to clarify the effects of nutritional status on digoxin pharmacokinetics. The present study established important sources of variability in digoxin pharmacokinetics and highlighted the relationship between pharmacokinetic parameters and nutritional status in hospitalized Korean patients.
在住院患者中安全有效地使用地高辛需要了解该药物的药代动力学以及各种因素对药物处置的影响。然而，尚未有人尝试将个体的地高辛需求量与营养状况联系起来。
本研究的主要目标是估算地高辛的群体药代动力学，并确定能够解释韩国住院患者药代动力学变异性的营养状况。
回顾性收集了首尔国立大学盆唐医院106例接受口服地高辛治疗患者的常规治疗药物监测数据。使用非线性混合效应建模工具（NONMEM）和多次谷浓度筛选方法，通过单室开放标签药代动力学模型对地高辛的药代动力学进行分析。
探讨了人口统计学特征以及生化和营养指标的影响。使用NONMEM生成的估算结果表明，地高辛的清除率/表观分布容积（CL/F）受肾功能、血清钾、年龄和理想体重百分比（PIBW）的影响。这些影响可以通过以下公式进行建模：CL/F（L/h）= 1.36 ×（肌酐清除率/50）（1.580）× K（0.835）× 0.055 ×（年龄/65）×（PIBW/100）（0.403）。CL/F的个体间变异系数（%CV）为34.3%，观察浓度与预测浓度之间 的残余变异（SD）为0.225 μg/L。自抽样程序得出的中位数估算值具有可比性，且在NONMEM估算值的5%以内。与验证组的相关性分析显示观察值与预测值之间呈线性相关。
在常规治疗药物监测中使用该模型需要满足某些条件，这些条件与本研究中各亚组的条件一致。因此，需要进一步研究以阐明营养状况对地高辛药代动力学的影响。本研究确定了地高辛药代动力学变异性的重要来源，并突出了韩国住院患者药代动力学参数与营养状况之间的关系。
