Population Pharmacokinetics of Digoxin in Duchenne Muscular Dystrophy (DMD) Patients.
Routine clinical pharmacokinetic data collected from Duchenne muscular dystrophy (DMD) patients receiving digoxin have been analyzed to evaluate the role of patients' characteristics for estimating dosing regimens. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of factors on digoxin clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the variables of body weight and combination with diuretics. The interindividual variability in digoxin clearance was modeled with proportional error with an estimated coefficient of variation of 25%, and the intraindividual variability in digoxin concentration was modeled with equal error with an estimated standard deviation of 0.0828 ng ml(minus sign1). In order to determine whether the population parameters obtained in this study were accurate, we administered digoxin according to individual dosage regimens in four DMD patients, using these values obtained by the Bayesian method. As a result, we found that mean prediction error, which indicates the deviation of prediction accuracy for digoxin concentration in plasma, was small, as were mean absolute prediction error and root mean squared error, showing the accuracy of this prediction method. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.
Tateishi
Masato
M
Department of Clinical Pharmacology, Jichi Medical School, School of Medicine, Tochigi 329-04, Japan.
Ebihara
Akio
A