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| __NOTOC__
| | #REDIRECT [[Digoxin immune fab#Pharmacology]] |
| {{Digoxin immune fab}}
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| {{CMG}}; {{AE}} {{AK}}
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| '''''For patient information about Digoxin immune fab, click [[Digoxin immune fab (patient information)|here]].'''''
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| ==CLINICAL PHARMACOLOGY==
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| ===Mechanism of Action:===
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| DigiFab has an affinity for digoxin in the range of 109 to 1010 M-1, which is greater than the affinity of [[digoxin]] for its sodium pump receptor, the presumed receptor for its therapeutic and toxic effects. When administered to the intoxicated patient, DigiFab binds to molecules of digoxin reducing free digoxin levels, which results in a shift in the equilibrium away from binding to the receptors, thereby reducing cardio-toxic effects. Fab-digoxin complexes are then cleared by the kidney and [[reticuloendothelial system]].
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| ===Animal Studies:===
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| No toxic effects were observed when DigiFab was administered to healthy male Sprague Dawley rats in equimolar doses sufficient to neutralize a 1 mg/kg dose of digoxin. In these studies, the physiologic changes produced by toxic serum concentrations of digoxin were ameliorated rapidly by the administration of DigiFab, or another ovine digoxin-specific immune Fab, Digibind® (manufactured by GlaxoSmithKline). Statistically equivalent responses were observed with both DigiFab and Digibind to the following variables: PTQ index, heart rate, mean arterial pressure, ventilation, arterial blood gases, and serum potassium concentrations.
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| ===Clinical Pharmacokinetics:===
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| The pharmacokinetics of DigiFab were assessed in a randomized and controlled study of DigiFab and Digibind (comparator Fab product for treatment of digoxin toxicity). Sixteen healthy subjects were given 1 mg of intravenous digoxin followed by an approximately equimolar neutralizing dose of either DigiFab (n=8) or Digibind (n=8). The pharmacokinetic profiles of Fab were similar for both products.1 The similar volumes of distribution (0.3 L/kg and 0.4 L/kg for DigiFab and Digibind, respectively) indicate considerable penetration from the circulation into the extracellular space and are consistent with previous reports of ovine Fab distribution, as are the elimination half-life values (15 hours and 23 hours for DigiFab and Digibind, respectively).2-6 The elimination half-life of 15-20 hours in patients with normal renal function appears to be increased up to 10 fold in patients with renal impairment, although volume of distribution remains unaffected.6
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| ===Clinical Studies:===
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| There have been two controlled clinical trials conducted with DigiFab: a pharmacokinetic and pharmacodynamic study of DigiFab as compared to Digibind in healthy volunteers, and a prospective multi-center study of the efficacy of DigiFab in patients presenting with life-threatening digoxin toxicity.
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| The objective of the pharmacokinetic and pharmacodynamic study was to compare these parameters for DigiFab to those for Digibind.1 This trial was conducted in healthy volunteers who were administered a 1 mg intravenous dose of digoxin, followed 2 hours later by an equimolar neutralizing dose of either DigiFab or Digibind. The pharmacokinetics of both digoxin and Fab were determined (see Clinical Pharmacokinetics for Fab pharmacokinetic parameters). The primary outcome measure was the serum level of free (unbound) digoxin. The results demonstrated that both products reduced the level of free digoxin in the serum to below the limit of assay quantitation for several hours after Fab administration. Cumulative urinary excretion of digoxin was comparable for both products and exceeded 40% of the administered dose by 24 hours. These results demonstrate that DigiFab and Digibind have equivalent pharmacodynamic effects on the digoxin parameters that are relevant to the treatment of digoxin toxicity. In this study, no patients developed a measurable immune response (human anti-ovine antibodies) to DigiFab.
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| The objective of the efficacy study was to demonstrate safety and also to determine the pharmacokinetics of, and clinical response to, DigiFab in patients. Results were compared to historical data on another U.S. marketed ovine digoxin immune Fab product, Digibind. Fifteen patients received doses of DigiFab based on its theoretical binding capacity for digoxin, and based on the known amount of digoxin ingested or on blood concentrations of digoxin at the time of admission. This study was conducted in both the U.S. and in Finland.
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| The primary outcome of the study was met in that serum free [[digoxin]] concentrations in all patients fell to undetectable levels following DigiFab administration. This was an expected outcome that is consistent with data in the literature showing that free digoxin concentrations fall rapidly following administration of Digibind.2 In the DigiFab trial, an independent blinded review of each patient's ECG showed that 10 of the 15 patients studied had ECG abnormalities that improved within 4 hours after the DigiFab infusion. The remaining 5 patients had ECG abnormalities that were unchanged from baseline throughout the 24-hour assessment period, and in one case through the 30-day follow up period. Although the reason for the lack of [[ECG]] resolution could not be clearly determined in all cases, it is possible that the ECG abnormalities observed in these patients were not entirely due to [[digoxin toxicity]], but rather to another underlying cardiac problem. Assessing all manifestations of toxicity, investigators classified 7 out of the 15 patients (47%) studied as having complete resolution of digoxin toxicity within 4 hours of DigiFab administration, and 14 patients (93%) were classified as having resolved their digoxin toxicity by 20 hours. The data for the proportion of patients who responded to treatment with DigiFab is similar to, and consistent with, historical data available for Digibind.2-3 In this study, where 2/15 patients had serum available for human anti-ovine antibody determination, there was no measurable immune response.
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| ==References==
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| {{Reflist|2}}
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| http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6832767f-db6b-4eea-b88b-bdfc905749e1
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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