Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis

Objective: The steady-state concentrations of digoxin at trough levels wire studied to establish the role of patient characteristics in estimating dos es for digoxin using routine therapeutic drug monitoring data. Method: The data (n = 448) showing steady state after repetitive oral admin istration in 172 hospitalized neonates and infants were analyzed using Nonl inear Mixed Effect Model (NONMEM), a computer program designed to analyze p harmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-s tate pharmacokinetic model. The effects of a variety of developmental and d emographic factors on the clearance of digoxin were investigated. Results: Estimates generated using NONMEM indicated that clearance of digox in (1.h(-1)) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variab ility in digoxin clearance was modeled with proportional errors with an est imated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precisi on) of the final population model tvas good (mean prediction error -0.04 ng .ml(-1); mean absolute prediction error 0.20 ng.ml(-1)).