A two-compartment population pharmacokinetic-pharmacodynamic model of digoxin in adults, with implications for dosage.
A population pharmacokinetic/pharmacodynamic model of digoxin in adult subjects was originally developed by Reuning et al in 1973. They clearly described the 2-compartment behavior of digoxin, the lack of correlation of effect with serum concentrations, and the close correlation of the observed inotropic effect of digoxin with the calculated amount of drug present in the peripheral nonserum compartment. Their model seemed most attractive for clinical use. However, to make it more applicable for maximally precise dosage, its model parameter values (means and SD's) were converted into discrete model parameter distributions using a computer program developed especially for this purpose using the method of maximum entropy. In this way, the parameter distributions became discrete rather than continuous, suitable for use in developing maximally precise digoxin dosage regimens, individualized to an adult patient's age, gender, body weight, and renal function, to achieve desired specific target goals either in the central (serum) compartment or in the peripheral (effect) compartment using the method of multiple model dosage design. Some illustrative clinical applications of this model are presented and discussed. This model with a peripheral compartment reflecting clinical effect has contributed significantly to an improved understanding of the clinical behavior of digoxin in patients than is possible with models having only a single compartment, and to the improved management of digoxin therapy for more than 20 years.
*Laboratory of Applied Pharmacokinetics, Department of Medicine, USC Keck School of Medicine; and †Department of Mathematics, University of Southern California, Los Angeles, California.
Roger W
RW
Jelliffe
Mark
M
Milman
Alan
A
Schumitzky
David
D
Bayard
Michael
M
Van Guilder
D000367:Age Factors; D001835:Body Weight; D002316:Cardiotonic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003198:Computer Simulation; D003404:Creatinine / Q000378:metabolism; D004077:Digoxin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D012737:Sex Factors
D002316:Cardiotonic Agents; D004077:Digoxin; D003404:Creatinine