Population pharmacokinetic investigation of digoxin in Japanese neonates

Objective: To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data. Method: The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (NONMEM), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated. Results: Estimates generated by NONMEM indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)(0.645) x Conc (ng/mL)(-0.724) x GA (weeks)(0.8). The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%. Conclusion: Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.