A Population Pharmacokinetic Analysis of the Influence of Nutritional Status of Digoxin in Hospitalized Korean Patients

Background: 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. Objectives: 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. Methods: 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. Results: 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 (MEW). These influences could be modeled by following the equation CL/F (L/h) = 1.36 x (creatinine clearance/50)(1.580) x K-0.835 x 0.055 x (age/65) x (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 mu g/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. Conclusions: 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. (C) 2014 Elsevier HS Journals, Inc. All rights reserved.