Ibutilide Fumarate

Ibutilide Fumarate is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm.Ibutilide is the first 'pure' class III antiarrhythmic drug to become available

Erythematous bullous lesions on the dorsa of the hands due to contact exposure to ibutilide fumarate for injection.[Pubmed:9692669]

Pharmacotherapy. 1998 Jul-Aug;18(4):880-2.

While waiting to observe the response to Ibutilide Fumarate by a patient with atrial fibrillation, a nurse preparing the intravenous solution inadvertently spilled the drug on the hands of a medical resident. The resident immediately wiped his hands dry with disposable paper towels. Several hours later he sensed tingling and itching over the area, and the next day two erythematous bullous lesions were present on the dorsal surfaces of both hands. A single application of topical steroid was applied to the affected areas. The lesions were kept clean and dry, and healed completely in approximately 10 days. This is an unusual allergic reaction due to contact with Ibutilide Fumarate.

Pharmacokinetic and pharmacodynamic properties of a single intravenous dose of ibutilide fumarate: a phase I, randomized, open-label, increasing-dose study in healthy Chinese men.[Pubmed:18035195]

Clin Ther. 2007 Sep;29(9):1957-66.

BACKGROUND: Atrial flutter is a common sustained atrial tachyarrhythmia whose frequency increases with age. Ibutilide is a class III antiarrhythmic agent used for the cardioversion of atrial flutter or atrial fibrillation. OBJECTIVE: This study assessed the pharmacokinetic (PK) and pharmacodynamic properties and tolerability of a single intravenous dose of Ibutilide Fumarate in healthy Chinese men. METHODS: This Phase I, randomized, open-label, increasing-dose trial was conducted at the Clinical Pharmacology Center, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking men aged 18 to 45 years and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 6 treatment groups: ibutilide 0.005, 0.01, or 0.02 mg/kg, or 0.5, 0.75, or 1.0 mg. Each volunteer received a 10-minute infusion of ibutilide under fasting conditions. For analysis of PK properties, blood samples were obtained at the following times: immediately before administration of study drug; 3, 5, 8, 10, 30, and 60 minutes after administration; and 2, 4, 6, 8, 12, and 24 hours after administration. Plasma ibutilide concentrations were determined using a validated high- performance liquid chromatography method with tandem mass-spectrometric detection. Continuous electrocardiographic monitoring was performed, and 12-lead electrocardiograms were recorded before dosing and at defined times from the start of infusion until 24 hours after dosing. Tolerability was assessed throughout the study based on physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse effects. RESULTS: Forty healthy Chinese men were enrolled (mean [SD] age, 24.0 [3.9] years [range, 19-36 years]; mean [SD] body weight, 62.8 [7.9] kg [range, 48- 80 kg]). The plasma ibutilide end-of-infusion concentration and AUC(0-infinity) increased approximately linearly with increasing doses of ibutilide. No statistically significant differences in the principal PK parameters were found among dosage groups; t(1/2) ranged from 7.5 to 9.1 hours, systemic clearance from 68 to 85 mL/min per kg, and Vd from 51 to 60 L/kg. The mean QTc interval was significantly increased during and after ibutilide infusion (baseline range, 406-418 milliseconds; maximum range, 469-683 milliseconds; P < 0.05 vs baseline). The changes in QTc interval were dose dependent, and there was a significant correlation between plasma ibutilide concentrations and changes in the QTc interval (r = 0.7244; P < 0.01). There were no significant changes in blood pressure or the QRS and PR intervals. One volunteer complained of dizziness, but no other apparent adverse effects were observed. CONCLUSIONS: The results of this study in a selected population of healthy Chinese men suggest that the PK properties of ibutilide are linear with respect to dosing. A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration- dependent manner. Ibutilide was generally well tolerated.

Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery.[Pubmed:10421596]

Circulation. 1999 Jul 27;100(4):369-75.

BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a cause of significant morbidity and increased hospital costs, yet there is no well-studied treatment strategy to deal with them expeditiously. The purpose of this study was to determine the efficacy and safety of Ibutilide Fumarate, an approved drug for the rapid conversion of atrial fibrillation and flutter, in patients after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or 1.0 mg of Ibutilide Fumarate. Treatment was considered successful if sinus rhythm was restored for any period of time by hour 1.5. A total of 302 patients were randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide resulted in significantly higher conversion rates than placebo, and efficacy was dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%). Conversion rates at all doses were higher for atrial flutter than for atrial fibrillation. Mean time to conversion decreased as the dose was increased. Polymorphic ventricular tachycardia was the most serious adverse effect and occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment alternative for the atrial arrhythmias that occur after cardiac surgery.

Developmental toxicity of ibutilide fumarate in rats after oral administration.[Pubmed:8987159]

Teratology. 1996 Sep;54(3):157-64.

In two Segment II Teratology studies, timed-pregnant Crl:CD[BR] (Sprague-Dawley) rats were treated orally (gastric intubation) on days 6-15 of gestation with Ibutilide Fumarate (ibutilide), a class III antiarrhythmic that has been shown to increase the refractory period and action potential duration of myocardial cells. In the first study, ibutilide does of 20, 40, and 80 mg/kg/ day were tested. Although maternal toxicity was equivocal in the 80 mg/kg/day group, all 23 rats that conceived had entirely resorbed liters when the animals were killed on day 20 of gestation. Similarly, 12 of 24 litters were completely resorbed in the 40 mg/kg/day group, with an 87.7% postimplantational loss. Of the surviving fetuses in this group, 48.6% had at least one malformation. The incidences of malformed pharynx and malformed palate, along with adactyly, were statistically significantly higher in this group than in the control group. In addition, a significant (P < 0.05) increase in total malformations (5.7% of the fetuses), relative to the controls (0.8%), was found for the 20 mg/kg/day group. Since a no observed adverse effect level (NOAEL) was not found, a second teratology study was performed. In this study, the ibutilide doses were 5, 10, and 20 mg/kg/day. The 20 mg/kg/day dose was again teratogenic with 9.2% of the fetuses malformed, as compared to a control value of 1.0%. Also, the incidences of scoliosis and interventricular septal defect were statistically significantly higher in this group. Although statistically significant differences were not detected, scoliosis was also found in the 10 mg/kg/day group (3 fetuses in 2 litters), along with a significant dose-response trend for this malformation. As the result, the NOAEL for ibutilide teratogenicity in rats was set at 5 mg/kg/day. This dose is 4 times the proposed maximum clinical dose (two 1 mg doses, each infused over 10 minutes, or 0.033 mg/kg for a 60 kg person), when corrected for 2.6% oral bioavailability in the rat at a dose of 10 mg/kg, as determined in separate studies.

Structural determinants of HERG channel block by clofilium and ibutilide.[Pubmed:15266014]

Mol Pharmacol. 2004 Aug;66(2):240-9.

Block of human ether-a-go-go related gene (HERG) K(+) channels by a variety of medications has been linked to acquired long QT syndrome, a disorder of cardiac repolarization that predisposes to lethal arrhythmias. The drug-binding site is composed of residues that face into the central cavity of the channel. Two aromatic residues located on the S6 domain (Tyr652 and Phe656) are particularly important structural determinants of drug block. The role of pore helix residues (Thr623, Ser624, Val625) is less clear. In this study, we compared the pharmacological properties of two structurally related compounds, ibutilide and clofilium. Both compounds are charged amines with a single phenyl ring. Clofilium, a chlorobenzene derivative, is a potent blocker of HERG channels, but has a remarkably slower time course for recovery from block than ibutilide, a methanesulfonanilide. The difference in the rate of recovery from block can be explained simply by variation in drug trapping. There is little recovery from clofilium block with D540K HERG channels that permit untrapping at hyperpolarized potentials. Alanine-scanning mutagenesis of the S6 domain and a portion of the pore helix revealed that the binding site residues were the same for both compounds. However, S624A, located at the base of the pore helix, was the only HERG mutation that enabled rapid recovery from clofilium block. In summary, the pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen (e.g., clofilium) or a methanesulfonamide (e.g., ibutilide).

Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel.[Pubmed:9655836]

J Pharmacol Exp Ther. 1998 Jul;286(1):9-22.

This study examined the ionic mechanism of ibutilide, a class III antiarrhythmic in clinical use, on freshly isolated human atrial cells. Cells had resting potentials of -71.4 +/- 2.4 mV, action potentials with overshoot of 36.8 +/- 1.8 mV, duration of 265 +/- 89 msec at 90% repolarization and slow repolarization (n = 16). Ibutilide, at 10(-7) M, markedly increased action potential duration. Four types of outward currents were detected: Ito, Iso, a delayed rectifier and IK1. Ibutilide had no inhibitory effect on these outward currents at 10(-7) M (n = 28). In K(+)-free solutions and -40 mV holding potential, mean peak inward current at 20 mV was -1478 +/- 103 pA (n = 12). Ibutilide increased this current to -2347 +/- 75 pA at 10(-7) M, with half maximal effect (Kd) of 0.1 to 0.9 nM between -10 and +40 mV (n = 21). At similar concentrations, the drug increased APD, with Kd of 0.7 and 0.23 nM at 70 and 90% repolarization, respectively (n = 8). Ibutilide shifted the mid-point of the steady-state inactivation curve from -21 to -12.2 mV (n = 6), and reduced current decline during repetitive depolarization (n = 5). The drug induced inward current was carried by Na+o through a nifedipine inhibited inward channel because Na+o removal eliminated the effect, and nifedipine abolished the inward current and the drug induced APD prolongation. We propose that a Na+ current through the L-type Ca++ channel mediates ibutilide's potent clinical class III antiarrhythmic action.

Ibutilide fumarate is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm.

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