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

Abstract

Background: Safe and effective use of digoxin in the hospitalized populations requires information about the drugs pharmacokinetics and the influence of various factors on drugs disposition. However, no attempts were made to link an individuals digoxin requirements with nutritional status. Objectives: The main goal of this study is to estimate the population pharmacokinetics of digoxin and identify 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 was analyzed with a one-compartment open pharmacokinetic model using Nonlinear Mixed Effects Modeling (NONMEM) and a multiple trough screen approach. Results: The effect of demographic characteristics, and biochemical and nutritional indices were explored. Estimates generated by NONMEM indicated that apparent clearance (CL/F) of digoxin was influenced by the renal function, serum potassium, age, and percent of ideal body weight (PIBW). These influences could be modeled by following equation CL/F (L/h) = 1.36 (CCR/50)1.580  K0.835  0.055 (AGE/65)  (PIBW/100)0.403. The inter-individual variability (CV) for CL/F was 34.3% and the residual variability (SD) between observed and predicted concentrations was 0.225 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. Discussion: The use of this model in routine TDM requires that certain conditions be met that are consistent with the conditions of the sub-populations in the present study. Therefore, the authors advocate further studies to elucidate the effects of various nutritional status on digoxin pharmacokinetics. Conclusion: The present study established important sources of variability in digoxin pharmacokinetics and showed the relationship between pharmacokinetic parameters and nutritional status in hospitalized Korean patients.