Digoxin pharmacokinetics: Role of renal failure in dosage regimen design

Abstract

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.

Estimation of Pharmacokinetic Parameters Based on the Patient-Adjusted Population Data

“…Therefore, the following population relationship may be constructed for this drug: Similar relationships have been reported for some drugs that are therapeutically monitored. For example, the following relationship was reported 5 for digoxin in 10 subjects with different degrees of renal function:…”

“…For instance, population data indicate that there is a significant relationship between the clearance (CL) of digoxin and the creatinine clearance (a measure of how well the kidneys function). 4,5 As creatinine clearance (CL CR ) decreases, so does the clearance of digoxin. One can actually use the reported population-based relationship for digoxin to estimate a clearance value in an individual patient based on his/her creatinine clearance.…”

Monitoring digoxin therapy: III. How useful are the nomograms?

“…The apparent Vd of digoxin varies widely being 420 to 1026 1 (Koup, Greenblatt, Jusko, Smith & Koch-Weser, 1975) in normal individuals, while in patients with renal failure it may be reduced, the range (189-481 litre) overlapping with that of subjects with normal renal function (Koup, Jusko, Elwood & Kohli, 1975). There is also evidence that the apparent Vd may be altered in the elderly (Ewy, Kapadia, Yao, Lullin & Marcus, 1969), in infants (Morselli, Assael, Gomeni, Mandelli, Marini, Reali, Visconti & Sereni, 1975) and in patients with thyroid disease (Doherty & Perkins, 1966).…”

Digoxin Therapy: Textbooks, Theory and Practice

“…In renal failure there is a lowered apparent volume of distribution of digoxin (Koup, Jusko, Elwood & Kohli, 1975) and the available data suggest that this may also be the case in hypothyroidism (Doherty & Perkins, 1966); this lowered apparent volume of distribution is another factor apart from decreased renal elimination of digoxin which may result in higher plasma levels than would occur following the same dose in the absence of renal failure but the significance of the elevation due to abnormal distribution is not fully understood. Digoxin is widely distributed throughout the tissues of the body being chiefly concentrated in the heart, kidneys, liver and skeletal muscle (including diaphragm) (Doherty, Perkins & Flanigan, 1967); it is not, however, distributed into fat (Ewy, Groves, Ball, Nimmo, Jackson & Marcus, 1971).…”