Pharmacokinetic Aspects of Digoxin-Specific Fab Therapy in the Management of Digitalis Toxicity

Abstract

Digoxin intoxication occurs frequently and may require treatment with digoxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0.40 L/kg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to 10-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approximately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration. More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological membranes, it can sequester tissue-bound and intracellular digoxin into the extracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity. The pharmacokinetic fate of total digoxin after administration of digoxin-specific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin concentrations, however, is delayed by 12 to 130 hours in patients with renal dysfunction and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concentration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin concentrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains it capability of binding digoxin while it resides in plasma. There is no evidence to support a dissociation between the Fab-digoxin complex over extended periods of time.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

“…However, the renal elimination of macromolecules is subject to the limitations of the molecular weight and the conformation, among other factors (14). Small proteins such as insulin, human growth hormone, and antibody Fab fragments are excreted in the urine (15)(16)(17). Catabolic breakdown of large protein molecules, either systemically or locally in kidney tissues, often precedes urinary excretion (15,18,19).…”

Massive ingestion of cardiac drugs: toxicokinetic aspects of digoxin and sotalol during hemofiltration

“…1A). 5 This is a consequence of redistribution of digoxin from the periphery to the circulation. Concurrently, we see a marginal decrease in free digoxin level, followed by an increase, probably reflecting the mobilization of digoxin from the tissues to the circulation, and a subsequent decrease.…”

“…Digoxin-specific Fab fragments have a molecular weight of approximately 46 kDa and are cleared by the native kidney. 5 Though the nominal pore size of the CVVH filter is 70 kDa, in vivo pore size is much lower because of the formation of a protein layer on the membrane. This case shows that the digoxin-specific Fab fragments do not pass the ultrafiltrate membrane.…”

PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice

“…The simulated behavior of topotecan in the presence of 8C2 is quite similar to the observed profile of digoxin disposition following treatment of patients with anti-digoxin Fab (for treatment of digoxin intoxication). Patients often demonstrate a rebound increase in unbound digoxin concentrations, after an initial decrease in unbound digoxin concentrations, which results in the recurrence of digoxin toxicities (Ujhelyi and Robert, 1995; Ujhelyi et al, 1993). Although the model predicts a complex relationship between antibody dosing and effects, the simulations support the use of 8C2 in the proposed inverse targeting strategy to decrease the systemic toxicity of IP topotecan.…”