Single‐ and multiple‐dose kinetics of intravenous digoxin

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across‐dose kinetic profile was determined for each subject. After a 6‐mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single‐ and multiple‐dose trials were as follows: elimination half‐life (t½), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = −0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t½, 40.9 and 37.9 hr (r = −0.14). Mean observed and predicted predose steady‐state serum concentrations were 0.59 and 0.79 ng/ml (r = −0.02). Mean values of accumulation and elimination t½ were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = −0.64). Multiple‐dose digoxin therapy leads to no systematic change in digoxin clearance. Single‐dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple‐dose therapy. Clinical Pharmacology and Therapeutics (1980) 28, 340–345; doi: 10.1038/clpt.1980.171