Ibutilide Ibutilide A Class III Antiarrhythmic Drugs ZHANG Dai-fu Shanghai East Hospital Tongji University Tongji University September 10, 2010

  Classified as Class III according to Vaughan Williams Classification   Manufactured by Pharmacia & Upjohn, USA and approved by FDA in 1995   Approved by SFDA in 2007 Ibutlide

Chemistry Systematic name: Systematic name: N-(4-{4-[ethyl(heptyl)amino]-1- hydroxybutyl}phenyl)methanesulfonamide Formula: C 20 H 36 N 2 O 3 S Mol. Mass: g/mol

Mechanism of Action   Ibutilide prolongs action potential duration, so- called class III antiarryhthmic drug   The class III drugs block I Kr, the rapid component of delayed rectifier potassium current, thereby prolonging repolarization, the action potential duration, and the refractory period  does not  But ibutilide does not have a sodium-blocking, antiadrenergic, and calcium blocking activity

Mechanism of Action   Ibutilide activates slow sodium channel and promotes the influx of sodium, Its mechanism of action is unique among available class III drugs   Ibutilide may enhance the conductance of Ca ++ through the L- type calcium channel

Mechanism of Action +-+- V Max plateau Slow Na  (Ibutilide) Ca Na N T QT APD Action Potential Duration

Electrophysiologic Effects   No clinically significant effect on QRS   Produces a dose related prolongation of the QT interval   Prolongation of QT interval is similar in men and women   Prolongs action potential duration and effective refractory periods in both atria and ventricles

Electrophysiologic Effects   Lengthens effective refractory period in both atrium and ventricle   Enhances slow Na + inward plateau current and blocks delayed-rectifier outward K + current   Maintains Class III effects even at rapid heart rates

Hemodynamic Effects No clinically significant effects on cardiac output (CO), mean pulmonary arterial pressure (PAPm) or capillary wedge pressure (PCWP) in patients with ejection fractions > 35 or < 35%

Pharmacokinetics   Ibutilide is intravenously administered  It has a high first-pass metabolism, which results in a poor bioavailability when taken orally bioavailability  Individual pharmacokinetic properties are highly  Individual pharmacokinetic properties are highly viable Absorption

Pharmacokinetics   Ibutilide has a relatively large volume of distribution among individual subjects, which is about 11L/kg   Approximately 40% of the drug is bound with plasma albumin Distribution

Pharmacokinetics   Ibutilide has a high systemic plasma clearance that closes to the hepatic blood flow (29mL/min/kg).   Its metabolic pathway is via liver’s cytochrome P450 system   Only one in eight metabolites has active property of the Class III antiarrhythmic agents, and is only less than 10% of ibutilide Metabolism

Pharmacokinetics   After administration of ibutilide, it is quickly excreted by renal pathway with a half-life of approximately 6 hours   Approximately 82% metabolites is excreted in the urine, and The reminder of the drug is excreted in feces (about 19%) Excretion

Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29: Figure. Figure. Mean (SD) plasma concentration-time profiles after a single intravenous dose of ibutilide fumarate in healthy Chinese men

Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:

Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:

Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men

Figure. Figure. Mean (SD) QTc intervals after a single intravenous dose of ibutilide fumarater in healthty Chinese men Clin Ther. 2007;29: Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men

  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   Ibutlide was well tolerated Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Summary Clin Ther. 2007;29:

Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):

Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):

Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):

Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5 Clinical Trial

Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5

Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5

Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF JACC. 1998; 31: Clinical Trial

Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF Figure. Mean chang from baseline in systolic and diastolic blood Pressure and in pulse rate in Ibutilide- and procainamide-treated patient JACC. 1998; 31:1414-9

Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59: Clinical Trial

Int J Clin Pract. 2005;59: Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation

Int J Clin Pract. 2005;59: Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation

Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79: Clinical Trial

Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study JACC. 1996; 28:130-6 Clinical Trial

JACC. 1996; 28:130-6 Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study

Figure. The mean±SD change in corrected QT interval from the baseline interval at 1 h for patients receiving placebo and those receiving each dose of intravenous ibutilide infusion. A, Date for the groups as a whole. B, Date for patients with and without successful conversion to sinus rhythm *P≤0.00, P≤ JACC. 1996; 28:130-6 Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study

Pre-injection of magnesium sulfate enhances the efficacy of ibutilide for the conversion of typical but not of atypical persistent atrial flutter Int J Cardiol. 2010;141:260-5 Clinical Trial

Int J Cardiol. 2010;141:260-5 Pre-injection of magnesium sulfate enhances the efficacy of ibutilide for the conversion of typical but not of atypical persistent atrial flutter

Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents JACC. 2004;44:864-8 Clinical Trial

Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents JACC. 2004;44:864-8

Indication   The rapid conversion of AF and AFL of recent onset to sinus rhythm   Patients with atrial arrhythmias of longer duration are less likely to respond to ibutilide fumarate   The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration

Usage Patient Weight Dose Second iv Infusion  60 kg iv infusion over 10 min. 1.0 mg (one 10 ml. Vial) If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. < 60 kg iv infusion over 10 min mg/kg ( 0.1 ml/kg) CORVERT product monograph

Dosing Post Cardiac Surgery Dosing Post Cardiac Surgery Patient Weight Dose Second iv Infusion  60 kg iv infusion over 10 min. 0.5 mg (5 ml) If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. < 60 kg iv infusion over 10 min mg/kg ( 0.05 ml/kg) CORVERT product monograph

Adverse effects Adverse effects Treatment-Emergent Medical Events with Frequency of More Than 1% and Higher Than that of placebo Ibutilide fumarate injecction insert. Revised 2009

Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9

Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9

Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9

Contraindication Patients with previous demonstrated hypersensitivity to ibutilide fumarate or any of the other product components

Warning   Before treatment of ibutilide, hypokalemia and hypomagnesemia should be corrected   Patients should be observed with continous ECG monitoring for at least 4 h

Ibutilide Summary   Conversion efficacy - AFL 60 – 80%, AF 30 – 50% - AF  arrhythmia duration (46% AF < 7 days vs. 18% AF  7 days)   Superior to iv procainamide, amiodarone, propafenone   Mean time to termination < 30 min.   Enhances efficacy of rapid pacing termination of AFL   Proarrhythmia risk (torsade de pointes) ˜ 2% sustained, 3% non-sustained