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Dofetilide
General information
Dofetilide is a pure Class III antidysrhythmic drug, without actions of any other class. It was developed following the observation that bis(arylalkyl)amines with methanesulfonamido moieties on both aryl groups prolong the cardiac action potential without significantly altering the maximum rate of depolarization [ ]. The pharmacology, clinical pharmacology, uses, adverse effects, and interactions of dofetilide have been reviewed [ ]. Cardiovascular adverse effects of dofetilide are the most troublesome. Other common effects have included mild headache, dizziness, dyspepsia, nausea, and vomiting [ ].
Pharmacology
Dofetilide is a highly selective blocker of the rapidly activating component of the inward rectifier potassium channel, I Kr [ ]. It therefore delays ventricular repolarization, which becomes less heterogeneous [ ], and prolongs the action potential duration and effective refractory period [ , , ]; it has the same effects in ventricular muscle in dilated cardiomyopathy and chronic ischemic cardiomyopathy [ ]. It has greater affinity for atrial than ventricular tissues in animals [ ], but probably not in man [ , ]. It preferentially blocks open channels and has Group 3 actions (SEDA-25, 209), with slow-onset kinetics [ ] and an increased likelihood of being prodysrhythmic at slower heart rates [ ].
Dofetilide causes a dose-related and plasma concentration-related prolongation of the QT c interval [ , , , ], and either reduces QT c dispersion [ ] or has no effect on it [ , ]. The effects on the QT c interval are rate-dependent, being greater at slower heart rates [ ]. Dofetilide does not usually broaden the QRS complex, but this was reported (and published twice) in a single patient with atrial fibrillation, in whom it was attributed to aberrant conduction [ , ].
During repeated oral administration of dofetilide 1.0–2.5 mg/day for 5 days the effect on the QT interval was slightly greater on day 1 than on day 5 at a range of plasma concentrations of about 1–4 ng/ml; this observation suggests the occurrence of tolerance, but in that case one would have expected a clockwise hysteresis loop in the effect concentration curve, and no hysteresis was seen either after a single dose or at steady state [ ].
Dofetilide has a small positive inotropic effect in animal hearts [ , ]. In a double-blind, placebo-controlled study of oral dofetilide 125, 250, or 500 mg bd for the maintenance of sinus rhythm after cardioversion of sustained atrial fibrillation or flutter in 201 patients, there were small changes in echocardiographic measures of atrial contractility, but no changes in stroke volume or cardiac output [ ].
Clinical pharmacology
The pharmacokinetics of dofetilide are linear after single oral doses of 2–10 micrograms/kg [ , ] and repeated doses of 1.0–2.5 mg/day [ ]. Dofetilide is well absorbed (about 90%) after oral administration [ , , ]. Its absorption is relatively slow and peak concentrations are not reached for 1–2.5 hours; absorption is slower after food. It is a low clearance drug, with a clearance rate of about 6 ml/minute/kg, and has a volume of distribution of about 3 l/kg [ , ]. It is mostly excreted unchanged by the kidneys, with a half-life of about 8 hours. Its clearance is therefore roughly proportional to creatinine clearance, particularly at high rates of clearance. A small proportion is metabolized in the liver by CYP3A4 to inactive metabolites [ ].
In a pharmacokinetic–pharmacodynamic study in 10 healthy volunteers intravenous dofetilide 0.5 mg caused a mean maximum prolongation of the QT c interval of 121 ms and the mean plasma concentration associated with half-maximal effect was 2.2 ng/ml [ ].
Uses
Dofetilide has been used to convert atrial fibrillation and atrial flutter to sinus rhythm, in maintaining sinus rhythm thereafter, in suppressing paroxysmal supraventricular tachycardia, inducible atrioventricular nodal re-entry tachycardia, and inducible sustained ventricular tachycardia, in suppressing the dysrhythmias of the Wolff–Parkinson–White syndrome, and in facilitating conversion of ventricular fibrillation.
Drug studies
Observational studies
In 19 patients with atrial fibrillation and five with atrial flutter, dofetilide 2.5–8.0 micrograms/kg caused conversion to sinus rhythm in 14 (10 with atrial fibrillation and four with atrial flutter) [ ].
In patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation, who had previously been unsuccessfully treated with 0–7 other drugs, intravenous dofetilide 3–15 micrograms/kg suppressed or slowed inducible ventricular tachycardia in 17 of 41 patients, compared with none of nine patients who received only 1.5 micrograms/kg [ ].
Intravenous dofetilide 2.5–5.0 micrograms/kg produced sinus rhythm in seven patients with paroxysmal atrial fibrillation of recent onset (under 7 days) and terminated paroxysmal supraventricular tachycardia in four of six patients [ ].
In patients with electrically inducible atrioventricular re-entrant tachycardia intravenous dofetilide 1.5–15 micrograms/kg had no effect on tachycardia inducibility at two lower doses but prevented the re-induction of tachycardia at three higher doses in 11 of 31 patients [ ].
Placebo-controlled studies
Conversion of atrial fibrillation and flutter
In a crossover, placebo-controlled study in 16 patients with recent onset atrial fibrillation, cardioversion was achieved in two of six patients who received dofetilide 8 micrograms/kg and in two of nine who received 12 micrograms/kg [ ]. None cardioverted with placebo. However, the average duration of atrial fibrillation was 35 days in those who cardioverted with dofetilide and 83 days in those who did not. The authors concluded that dofetilide had only limited effect in cardioverting atrial fibrillation of moderate duration.
In a double-blind, placebo-controlled study 98 patients, who developed atrial fibrillation/flutter within 1–6 days after coronary artery bypass graft surgery, were given dofetilide 4 or 8 micrograms/kg intravenously over 15 minutes [ ]. Eight of 33 patients converted to sinus rhythm after placebo, 12 of 33 after dofetilide 4 micrograms/kg, and 14 of 32 after dofetilide 8 micrograms/kg.
In a double-blind, placebo-controlled study in patients with sustained atrial fibrillation (n = 75) or atrial flutter (n = 16), dofetilide 8 micrograms/kg terminated the dysrhythmia in nine of 29 patients, compared with only four of 32 who received 4 micrograms/kg and none of 30 who received placebo [ ]. Patients with atrial flutter had a greater response to dofetilide (six of 11) than those with atrial fibrillation (five of 49).
In a placebo-controlled study in patients with atrial fibrillation or atrial flutter with a median dysrhythmia duration of 62 (range 1–180) days, there was conversion to sinus rhythm in 20 of 66 patients given dofetilide, compared with one of 30 patients given placebo [ ]. The conversion rate was higher in atrial flutter (seven of 11 patients) than in atrial fibrillation (13 of 55).
In a double-blind, placebo-controlled study in 325 patients with atrial fibrillation or flutter cardioversion, rates for dofetilide 125, 250, and 500 micrograms bd were 6.1, 9.8, and 30% respectively, compared with 1.2% with placebo [ ]. The probabilities of remaining in sinus rhythm at 1 year with dofetilide 125, 250, and 500 micrograms bd were 0.40, 0.37, and 0.58 respectively, and 0.25 for placebo.
In a double-blind, placebo-controlled study in 69 patients with atrial fibrillation or flutter, intravenous dofetilide 2–8 micrograms/kg caused conversion to sinus rhythm in 16 of 51 patients, compared with one of 18 who were given placebo; conversion of atrial flutter occurred in five of seven who were given dofetilide compared with none of three who were given placebo [ ].
In a randomized, placebo-controlled, crossover study in 15 men, mean age 34 (range 18–63) years, with Wolff–Parkinson–White syndrome and atrial fibrillation or atrioventricular re-entrant tachycardia induced electrophysiologically, six of ten patients who were given dofetilide converted to sinus rhythm, compared with one of five who were given placebo [ ]. There were no dysrhythmias.
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