Review

Review: The Pharmacology and Toxicology of Dofetilide

Edward W. Boyer MD PhD
The Children’s Hospital, Boston
Harvard Medical School
Boston, MA 02155

Christine Stork, PharmD
Central New York Poison Control Center
Syracuse, NY

Richard Y. Wang, D

Int J Med Toxicol 2001; 4(2): 16


Address for Correspondance

Edward W. Boyer MD PhD
Instructor in Medicine
The Children’s Hospital
Instructory in Pediatrics
Harvard Medical School
300 Longwood Avenue
Boston, MA 02155
e-mail: edward.boyer@tch.harvard.edu
Telephone: 617-738-0032

Financial Source

None

There are no financial, litigious, or other relationships that may lead to a conflict of interest, particularly with Pfizer, manufacturer of dofetilide (TikosynTM)

Introduction

Atrial fibrillation compromises cardiac output, increases ventricular filling pressures and causes thromboembolism; rapid ventricular rates may aggravate heart failure and cause cardiomyopathy. These findings suggest the desirability of sinus rhythm, but the relative benefits of cardioversion and maintenance of sinus rhythm compared against rate control and anticoagulation have not been established. All antiarrhythmic agents used for maintenance of sinus rhythm have the potential to precipitate life-threatening ventricular arrhythmias; most, when used in long-term therapy, are associated with an increased risk of death. Because of the benefits of sinus rhythm, the development of pharmacologic agents that restore sinus rhythm and improve survival has remained a priority. One such new agent is dofetilide (TikosynTM).

Recent studies suggest that dofetilide, when administered cautiously to selected patients, is effective for atrial fibrillation while carrying no additional risk of death. The safety of dofetilide has nonetheless been questioned. Specifically, dofetilide has a narrow therapeutic index and may cause torsades de pointes. In addition, dofetilide interacts significantly with a number of common medicines and foods. When dofetilide therapy is initiated, patients must be admitted to a monitored bed for a minimum of three days. Serum drug concentrations are not commercially available, even though dosing is based upon renal function. Initial clinical experience reported to the manufacturer demonstrates that therapeutic doses and overdose of dofetilide can lead to significant life-threatening arrhythmias and death. This paper reviews the pharmacology, pharmacokinetics, and toxicology of dofetilide.

Structure and Pharmacology

Pharmacology

Dofetilide (TikosynTM, Xelide, Figure 1), which is marketed by Pfizer, is a member of the methanesulfonanilide drug class. According to the Vaughan William standard, dofetilide exerts pure Class III antiarrhythmic activity. The chemical structure of dofetilide predicts the general characteristics of the drug, but not the high specificity of its action. It produces highly selective blockade of the ion channel carrying the rapid component of the delayed rectifier potassium current, Ikr. Dofetilide is a highly potent drug, which completely blocks Ikr channels at nanomolar concentrations. At clinically relevant concentrations, dofetilide has no effect on other repolarizing potassium currents, sodium channels ( Class I activity ), or alpha- and beta-adrenergic(Class II) receptors.8,9 Models of HERG1 (human ether-a-go-go-related gene) activity suggest that dofetilide is active only when in the reduced state.10

Dofetilide increases the monophasic action potential duration in a concentration-dependent manner, primarily via delayed repolarization.9,11,12 Surface ECG measurements demonstrate that dofetilide prolongs the QT interval without changing the duration of PR or QRS intervals . There is a direct linear relationship between the plasma concentration of dofetilide and the magnitude of QT interval prolongation. Prolongation of the corrected QT interval is maximal 2 hours after an oral dose of 500 micrograms and 10 minutes when the same dose is administered intravenously.13 Dofetilide has no effect on cardiac conduction velocity and sinus node function.11,12 Similarly, dofetilide exerts no effect on hemodynamic parameters in patients with normal or low left ventriclular ejection fraction.2

Other drugs of the methanesulfonanilide drug class such as ibutilide and sotalol have similar mechanisms of action but lack the high degree of specificity of dofetilide. Ibutilide inhibits the Ikr channel but, at picomolar concentrations, also activates inward sodium channels. Sotalol is also active at Ikr channels, but antagonizes beta-adrenergic receptors.

Pharmacokinetics

Absorption and Distribution

After oral administration, dofetilide is completely absorbed with high bioavailability (92-96%) that is unaffected by foods or antacids. Peak plasma concentrations occur within 3 hours of oral therapeutic dosing.13,14 The oral dose of dofetilide for the conversion of atrial fibrillation in adults is 500 micrograms twice a day. Steady state concentrations are achieved within 48 hours of repeated oral doses, even after dose escalation.15 Dofetilide has a large volume of distribution of 4L/kg and is well distributed to all tissue sites. After oral dosing, maximal clinical effects occur at 2 to 3 hours, which corresponds to peak serum concentrations that occur after a single dose.13-15

Metabolism and Elimination

Dofetilide is metabolized via a combination of hepatic and renal processes. Eighty percent of an ingested dose is excreted unchanged in the urine. The elimination half-life of dofetilide is 6.2 to 9.7 hours.16 Renal excretion is a first order process that occurs through a combination of glomerular filtration and cationic tubular secretion. Drugs and/or disease states that decrease rates of glomerular filtration or affect cationic tubular excretion are expected to increase serum dofetilide concentrations. The manufacturer recommends dosage adjustment for patients with a calculated creatinine clearance of less than 60 mL/min. Dofetilide is contraindicated in patients with a creatinine clearance of less that 20 mL/min.5 Sex-related differences in dofetilide metabolism exist. For example, women have been shown to have a 12 to 18% decreased clearance of dofetilide, even after adjustment for renal function.15,16

Twenty percent of an orally administered dose of dofetilide is hepatically metabolized, partially by the CYP3A4 isoenzyme. Inactive metabolites are formed by N-dealkylation and N-oxidation of the parent compound; they have been detected in urine but not plasma. Dofetilide has no appreciable inhibition of CYP3A4, CYP2D6, or CYP2D9 isoenzymes. Patients with mild to moderate hepatic failure do not exhibit increased serum dofetilide concentrations.5 There is no published clinical experience with pregnant or lactating women.

Clinical Efficacy

Two randomized, parallel, placebo-controlled, dose-response trials have evaluated the ability of dofetilide to: 1) convert patients with atrial fibrillation or atrial flutter of greater than one week duration to normal sinus rhythm; and 2) maintain normal sinus rhythm after chemical or electrical cardioversion. 2,17 In both studies, dofetilide resulted in a statistically significant, dose-related increase in the number of patients maintained in normal sinus rhythm, and delayed the time to recurrence of atrial fibrillation. Compared against placebo, dofetilide converted 32% of patients to normal sinus rhythm, versus 1% for placebo. Moreover, 71% of patients using oral dofetilide remained in normal sinus rhythm, compared against 26% on placebo therapy. Consequently, dofetilide is indicated and approved by the Food and Drug Administration for the chemical cardioversion of patients suffering from refractory atrial fibrillation, or to maintain normal sinus rhythm in recently converted patients.5

Patients taking dofetilide are at increased risk for polymorphic ventricular tachycardia (i.e., torsades de pointes) because this agent causes dose-related QT interval prolongation. Diminished creatinine clearance (less than 60mL per minute), a corrected QT interval greater than 460msec, and a dose greater than 500 micrograms twice daily are associated with an increased incidence for torsades de pointes.17

Although dofetilide treatment is associated with an increased incidence for torsades de pointes, clinical trials such as the DIAMOND-CHF (Danish Investigation of Arrhythmia and Mortality ON Dofetilide-Congestive Heart Failure) study (which found similar mortality rates between dofetilide and placebo groups) suggest the safety of dofetilide. 2,17-19 These findings must be interpreted with caution. To mitigate the risk of torsades de pointes, patients were excluded from the DIAMOND-CHF study if they had moderate prolongation of the baseline corrected QT interval, recent myocardial ischemia, bradycardia, hypokalemia, or severe renal failure.2 Furthermore, the dose of dofetilide was adjusted on the basis of renal function. Patients were admitted and monitored continuously for three days while dofetilide therapy was initiated. Despite these precautions, excessive prolongation of the QT interval (e.g., greater than 50% of baseline QT interval) forced termination of therapy in 2 percent of patients of patients that met inclusion criteria. Furthermore, torsades de pointes developed in 3 percent of the dofetilide group. Seventy-six percent of torsades occurred within the first three days of therapy; two episodes were fatal.2,3 Since ventricular arrhythmias occur early in therapy, the risk of morbidity and mortality is probably greatest shortly after dose initiation or increase. 3

Dofetilide should be used with caution in women. In the placebo-controlled premarketing trials of dofetilide, women had a 3.3 times greater risk for developing torsades as men.5 The difference between sexes may be due to greater expression of Ikr channels in adult women or the effect of estrogens on these channels.20 Although women that received dofetilide did not demonstrate an increased mortality compared with women receiving placebo, mortality differences have not been specifically investigated in studies to date.5

Class III antiarrhythmic agents are potential human teratogens because of their ability to induce bradycardia in the embryo during organogenesis. Studies in the rat identified concentration-dependent bradycardia, as well as cleft palate, limb hypoplasia, dilation of cerebral ventricles, and vertebral abnormalities. Dofetilide is listed in Pregnancy Category C; consequently, dofetilide should be administered to pregnant women only if the benefit to the patient justifies the potential risk to the fetus.21

Dofetilide has significantly greater efficacy than sotalol both in terms of converting and maintaining normal sinus rhythm. The efficacy and safety of dofetilide has not been directly compared against other methanesulfonanilide drugs such as ibutilide.

Drug Interactions

Dofetilide is anticipated to exhibit numerous drug-drug and drug-food interactions. Verapamil, but not other calcium channel blockers, competes with dofetilide in binding to Ikr channels during repolarization, and may therefore potentiate QT interval prolongation.22 There are numerous potential agents which are theoretically contraindicated due to potential pharmacodynamic interactions. For instance, agents that prolong the QTc interval on ECG may be potentially dangerous when coadministered with dofetilide. Potentially dangerous drugs include erythromycin, clarithromycin, aliphatic and piperidine phenothiazines, and tricyclic antidepressants. In addition, other Type III antidysrhythmics (e.g., ibutilide, sotalol, amiodarone), Type I antidysrhythmics (e.g., quinidine, propafenone, flecainide), antimalarials, and propoxyphene may interact significantly with dofetilide. Cimetidine decreases renal excretion of dofetilide by inhibiting the cationic transport system, thereby increasing serum dofetilide concentrations.23 The cationic transport mechanism of the renal tubule is also inhibited by ketoconazole, prochlorperazine, trimethoprim, and megestrol; coadministration of these drugs may consequently raise serum dofetilide concentrations.5 In vitro studies have demonstrated that dofetilide can be metabolized by CYP3A4, although this is not a common metabolic pathway. Nonetheless, administration of drugs that inhibit this cytochrome may also increase dofetilide concentration.5

Toxicicology

Animal Toxicity Data: Dofetilide was well tolerated in animal toxicity studies. Prolongation of the effective refractory period in myocardial cells was the major toxic effect produced.. 9,11,12

Human Toxicity Data: Overdose experience is minimal to date, with two cases having been reported in clinical studies. The first case involved the ingestion of 28 500-microgram capsules. The patient was treated with gastric lavage approximately 30 minutes following the ingestion, received no additional gastric decontamination and suffered no adverse events.5,6 The second involved a patient who inadvertently received two 500 microgram doses approximately one hour apart. The patient suffered ventricular fibrillation and cardiac arrest two hours after the second dose. It is unclear if any therapy, including gastrointestinal decontamination, was attempted.6

Overdose Management

Activated charcoal is an effective method of gastrointestinal decontamination when administered rapidly after the ingestion of dofetilide. An open label, randomized, three-way crossover study performed on healthy volunteers demonstrated a statistically significant decrease in Cmax and AUC when activated charcoal was administered 15 minutes after dofetilide as compared to values when dofetilide was administered alone or charcoal was administered 4 hours after dofetilide.6 Furthermore, the increase in the QT and QTc intervals was smaller for subjects given charcoal 15 minutes after the dofetilide dose. There was no statistical difference for Cmax and AUC for patients receiving charcoal 4 hours following dofetilide compared to patients that received dofetilide alone.6 Rapid administration of activated charcoal following dofetilide administration therefore decreases absorption as well as the clinical effects of dofetilide.6

There is no known antidote to dofetilide. Treatment of overdose consists of rapid gastrointestinal decontamination with single-dose activated charcoal, continuous cardiac monitoring, serial electrocardiographic evaluation, and aggressive supportive care. Since the most predominant manifestation of toxicity is likely to be corrected QT interval prolongation or torsades de pointes, specific therapy should be directed toward preventing or reversing these abnormalities.. Serum potassium and magnesium concentrations should be closely monitored. Since hypokalemia and hypomagnesemia increase the susceptibility to torsades de pointes, they must be corrected if present. Serial electrocardiograms should be performed and if the corrected QT interval is prolonged (e.g., greater than 460 milliseconds), empiric magnesium sulfate administration is recommended. Animal studies have examined the effectiveness of magnesium sulfate and isoproterenol in treating torsades. Magnesium sulfate, administered prophylactically via oral or intravenous routes to dogs, was effective in the prevention of dofetilide-induced torsades.5 The benefits of prophylactic administration of magnesium sulfate to humans has not been determined. Similarly, isoproterenol infusion in conjunction with cardiac pacing attenuated the dofetilide-induced prolongation of refractory periods.5 Class Ia (e.g, quinidine, disopyramide, procainamide), class Ic (e.g., propafenone, encainide, flecainide), and class III (e.g., amiodarone, ibutilide, sotalol) antidysrhythmic agents are contraindicated in the treatment of dofetilide-induced dysrhythmias because they potentiate the inhibitory effect of dofetilide on Ikr channels. Overdrive pacing has also been proposed as therapy as treatment for dofetilide-induced torsades, but has never been formally studied.

There is no data concerning administration or overdose of dofetilide in the pediatric population. Pediatric patients who ingest any amount of dofetilide should receive rapid gastrointestinal decontamination, admitted for continuous cardiac monitoring, and expectantly managed for torsades.

Special Considerations

Because of its significant potential for toxicity as well as the large number of drug interactions, dofetilide receives special handling in terms of initiating therapy and refilling prescriptions. Dofetilide is available only to hospitals that have received manufacturer-provided education regarding dosing and initiating therapy. Dofetilide must be initiated in a facility that "can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation."5 Patients are admitted for a minimum of three days continuous cardiac monitoring. On discharge, patients receive close monitoring of QT interval and creatinine clearance. Interestingly, dofetilide is available only through the manufacturer; prescriptions may be written only by providers who have participated in specific educational programs. Once a prescription has been received, the manufacturer ships the medication directly to the patient.5

Conclusions

Dofetilide is a potent antiarrhythmic agent which carries the potential for significant morbidity and mortality in therapeutic dosing as well as overdose. Reports have demonstrated that adults who take relatively small overdoses may develop cardiac arrest. Until the range of toxicity of dofetilide is better defined, patients who ingest any amount of dofetilide should be admitted for continuous cardiac monitoring, serial electrocardiographic evaluation, rapid gastrointestinal decontamination, and supportive care. Patients may benefit from the administration of magnesium sulfate, either to reverse torsades or prevent its occurrence when the QT interval is prolonged.

Acknowledgement

We are indebted to Dr. Alfred Buxton and Dr. Chris Linden for their critical review of the manuscript.

  1. Flaker G, Blackshear J. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. Journal of the American College of Cardiology 1992; 20:527-32.
  2. Torp-Pedersen C, Moller M, Bloch-Thompson P, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. New England Journal of Medicine 1999; 341:857-65.
  3. Stevenson W, Stevension L. Atrial fibrillation in heart failure. New England Journal of Medicine 1999; 341:910-11.
  4. Grines C. Safety and effectiveness of dofetilide for conversion of atrial fibrillation and nesiritide for acute decompensation of heart failure: A report of the Cardiovascular and Renal Advisory Panel of the Food and Drug Administration. Circulation 2000; 101:e200-e201.
  5. Anonymous. Tikosyn (dofetilide) Capsules. Pfizer 1999. Accessed on: December 31, 2000. Available from: http//:www.tikosyn.com/prescriber/tikosyn_info_pre.htm.
  6. Tarasenko L. Overdose management for Dofetilide: Pfizer, 2000.
  7. Carmeliet E. Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. Journal of Pharmacology and Experiment Therapeutics 1992; 262:809-17.
  8. Duff H, Feng Z. High- and low-affinity sites for [3H]-dofetilide binding to guinea pig myocytes. Circulation Research 1995; 77:718-25.
  9. Gwilt M, Arrowsmith J, Blackburn K. UK-68798: A novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells. Journal of Pharmacology and Experiment Therapeutics 1991; 256:318-24.
  10. Ulens C, Tytgat J. Redox state dependency of HERGS631C channel pharmacology: relation of C-type inactivation. FEBS Letters 2000; 474:111-115.
  11. Jurkiewicz N, Sanguinetti M. Rate-dependent prolongation of cardiac action potentials by a methansulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circulation Research 1993; 72:75-83.
  12. Knilans T, Lathrop D, Nanasi P, al. e. Rate and concentration dependent effects of UK-68,798, a potent new class III antiarrhythmic, on canine Purkinje fibre action potential duration and Vmax. British Journal of Pharmacology 1991; 103:1568-72.
  13. Tham T, MacLennan B, Burke M, al e. Pharmacodynamics and pharmacokinetics of the class III antiarrhythimic agent dofetilide (UK-68,798). J Cardiovasc Pharmacol 1993; 21:507-512.
  14. LeCoz F, Funck-Bretano C, Morrell T, al e. Pharmocokinetic and pharmacodynamic modeling of the effects of oral and intravenous administration of dofetilide on ventricular repolarization. Clin Pharmacol Ther 1995; 57:533-542.
  15. Allen M, Nichols D, Oliver S. The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing. Brit J Clin Pharmacol 2000; 50:247-253.
  16. Smith D, Rasmussen H, Stopher D. Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog, and man. Xenobiotics 1992; 22:709-719.
  17. Pritchett E, Wilkinson E. Effect of dofetilide on survival in patients with supraventricular arrhythmias. American Heart Journal 1999; 138:994-997.
  18. Norgaard B, Wachtell K, Christiansen P, et al. Efficacy and safety in intravenously administered dofetilide in acute termination of atrial fibrillation and flutter: A multicenter, randomized, double-blind, placebo-controlled trial. American Heart Journal 1999; 137:1062-1069.
  19. Lindeboom J, Kingma J, Crijns H, Dunselman P. Efficacy and safety of dofetilide for rapid termination of atrial fibrillation and atrial flutter. The American Journal of Cardiology 2000; 85:1031-1033.
  20. Locati E, Zareba W, Moss A, Schwartz P, Vincent G, Lehmann M. Age- and sex-related differences in clinical manifestations in patients with congenital long QT syndrome. Circulation 1998; 97:2237-2244.
  21. Webster W, Brown-Woodward P, Snow M, Danielsson B. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity. Teratology 1996; 53:168-75.
  22. Zhang S, Zhou Z, Gong Q, Makielski J, January C. Mechanism of block and identification of the verapramil binding domain to HERG potassium channels. Circulation Research 1999; 84:989-998.
  23. Abel S, Nichols D, Christopher J, Eve M. Effect of cimetidine and ranitidine on pharmcokinetics and pharmacodynamics of a single dose of dofetilide. British Journal of Clinical Pharmacology 2000; 49:64-71.



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