Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

Butler, Vincent P.; Schmidt, Donald H.; Smith, Thomas W.; Haber, Edgar; Raynor, B. Denise; Demartini, P

doi:10.1172/jci108647

Cited by 82 publications

(20 citation statements)

References 35 publications

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“…The mean elimination half-times of 135 and 118 h found by two separate methods in this species ( Fig. 4 Prior studies ofthe effects of digoxin-specific IgG and Fab fragments on the pharmacokinetics of digoxin in the dog have documented substantial rises in plasma total digoxin concentration, with IgG causing about a sixfold greater rise than Fab (47). Analogous results were observed in the present rhesus monkey experiments.…”

Section: Resultssupporting

confidence: 83%

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Ochs¹,

Smith²

1977

J. Clin. Invest.

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A B S T R A C T The effects of Fab fragments of highaffinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10"0 M-1 as determined by equilibrium dialysis.Rapid second-order association kinetics (kf = 3.7x 106 M-1 per s) and slow dissociation kinetics (kr = 1.9 X 10-4 per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/ kg digitoxin intravenously developed ventricular tachycardia after 23±4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54 ± 16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135Dr. Ochs was a Fellow of Deutsche Forschungsgemeinschaft.Received for publication 20 January 1977 and in revised form 5 July 1977. and 118 h by radioimmunoassay and [3H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t1 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise let...

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Section: Resultssupporting

confidence: 83%

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Ochs¹,

Smith²

1977

J. Clin. Invest.

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“…Complementary studies in dogs showed a pronounced elevation of serum digoxin con centrations for up to 7 days in most animals treated with intact specific sheep antibodies (7). Subsequently, there was a 50-to 100-fold decrease in serum digoxin within 48-72 h, indicating tissue uptake of released digoxin and increased urinary excretion of digoxin in un bound form, due to immunologically mediated degradation of the heterologous antibody.…”

Section: Alterations Of Digoxin Pharmacokinetics By Specific Antibodiesmentioning

confidence: 94%

Reversal of Digitalis Effects by Specific Antibodies

1979

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Highly digoxin-specific or ouabain-specific antibodies can readily be obtained by immunizing rabbits or sheep with repeated injections of the glycoside coupled to protein carriers. By virtue of their binding capacity digoxin-specific antibodies are capable of removing digoxin concentrations from red blood cells and renal tissue specimens. As evidenced by various experiments with human erythrocytes and isolated cardiac preparations in vitro, digoxin effects are rapidly reversible in the presence of digoxin-specific antibodies. In vivo antidigoxin antibodies can protect animals from toxic digoxin effects and promptly abolish established toxic effects, associated with marked alterations of digoxin pharmacokinetics. However, due to the large molecular weight, complete antibodies cannot be eliminated via the renal route. The use of antigen-binding (Fab) fragments of digoxin-specific antibodies offer the advantage of rapid renal elimination of bound and inactivated digoxin. So far, due to potential immune reactions, the clinical use of purified digoxin-specific antibodies or Fab fragments is restricted to life-threatening accidental or suicidal digoxin or digitoxin poisoning.

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“…Data from baboons and dogs indicate that Fab has a larger volume of distribution than its parent IgG molecule, and is renally eliminated via glomerular filtration with an elimination half-life of 5 to 12 hours. [5,6] The plasma concentration-time profile of Fab is biexponential, fitting a classic 2-compartment pharmacokinetic model ( fig. 1).…”

Section: Pharmacokinetics Of Digoxin-specific Fobmentioning

confidence: 99%

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

Ujhelyi

Robert

1995

Clinical Pharmacokinetics

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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)

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Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

Cited by 82 publications

References 35 publications

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

Reversal of Digitalis Effects by Specific Antibodies

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

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