Digoxin toxicity is dose-dependent. A vial of 40 mg digoxin-Fab is capable of neutralising 0.5 mg digoxin [5]. Digoxin-Fabs predominantly bind digoxin in the circulation, but they may also diffuse into the interstitial space, binding digoxin there. The affinity of digoxin to digoxin-Fabs is 100- to 1000-fold higher than for its target, the Na+/K+-ATPase pump [7], causing digoxin to dissociate from its binding sites with a dissociation half-life of about 1 h [10]. A concentration gradient is established, which facilitates movement of dissociated digoxin into the interstitial and intravascular space [7, 8, 11]. Ventricular arrhythmias usually start to resolve within a few minutes after digoxin-Fab administration and, in general, the time required for reversal of digoxin-induced rhythm and conduction disturbances is reported to be 30–45 min [7, 11].

After digoxin-Fab administration, free and unbound serum digoxin concentrations will drop to near zero. However, the total serum digoxin concentration will increase rapidly (8- to 20-fold in patients with normal kidney function and up to 33-fold in those with impaired kidney function [12]), reflecting pharmacologically inactive digoxin bound to digoxin-Fabs and the continuous binding of redistributed digoxin from extravascular tissue stores to the plasma [2, 4, 7]. Free digoxin serum concentrations remain low for a considerable period of time, depending on the digoxin-Fab dose, infusion technique and the patient’s renal function [7]. A rebound in free digoxin serum concentration can be seen 12–24 h after digoxin-Fab administration in patients with normal renal function, and may be delayed up to 24–96 h in patients with renal dysfunction and on average 130 h in end-stage renal disease [4, 7]. Fortunately, this amount of free digoxin redistributed from the tissues may not necessarily reflect a high tissue concentration or cause cardiac toxicity [4].

Dissociation of the digoxin/digoxin-Fab complex in the intravascular system is not expected over extended periods of time [4, 7, 11], as the affinity constant (Ka) between digoxin and digoxin-Fab is in the order of 1010 M−1 [11].

The elimination kinetics of the digoxin/digoxin-Fab complex is largely dependent on renal function, as glomerular filtration is permitted because the molecular weight of the digoxin-bound complex is below 60,000 Da [2, 10, 11]. In patients with renal failure, the plasma half-life of both digoxin (mean: 40 h) and digoxin-Fabs (15–20 h) is prolonged to over 100 h [5, 7]. In these patients, digoxin/digoxin-Fab complexes remain detectable in plasma for 2–3 weeks after digoxin-Fab administration [4, 11], but extracorporeal treatment for removal of the digoxin/digoxin-Fab complexes is not necessary [12]. In addition to the kidney, the reticuloendothelial system, which includes the liver, spleen and lymph nodes, is a potential site for catabolism of the digoxin/digoxin-Fab complexes [10, 11].