IbutilideIbutilide A Class III Antiarrhythmic Drugs

ZHANG Dai-fuZHANG Dai-fu

Shanghai East HospitalShanghai East Hospital Tongji UniversityTongji 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

IbutlideIbutlide

ChemistryChemistry

Systematic name:Systematic name: N-(4-{4-[ethyl(heptyl)amino]-1- hydroxybutyl}phenyl)methanesulfonamide

Formula: C20H36N2O3S 

Mol. Mass: 384.578 g/mol

Mechanism of ActionMechanism of Action Ibutilide prolongs action potential duration, so-called cl

ass III antiarryhthmic drug

The class III drugs block IKr, the rapid component of delayed rectifier potassium current, thereby prolonging repolarization, the action potential duration, and the refractory period

But ibutilide does notdoes not have a sodium-blocking, antiadrenergic, and calcium blocking activity

Mechanism of ActionMechanism 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 ActionMechanism of Action

+

-

V Max

plateau

Slow Na

(Ibutilide)CaN

a

N

TQT

APD

Action Potential Duration

Electrophysiologic EffectsElectrophysiologic 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 EffectsElectrophysiologic 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 EffectsHemodynamic 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%

PharmacokineticsPharmacokinetics

Ibutilide is intravenously administered

It has a high first-pass metabolism, which results It has a high first-pass metabolism, which results in a poor in a poor bioavailability when taken orally when taken orally

Individual pharmacokinetic properties are highlyIndividual pharmacokinetic properties are highly viable

AbsorptionAbsorption

PharmacokineticsPharmacokinetics

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

DistributionDistribution

PharmacokineticsPharmacokinetics

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

MetabolismMetabolism

PharmacokineticsPharmacokinetics

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;29:1957-66.

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;29:1957-66.

Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men

Clin Ther. 2007;29:1957-66.

Clin Ther. 2007;29:1957-66.

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;29:1957-66.

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

SummarySummary

Clin Ther. 2007;29:1957-66.

Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF

Am Heart J. 1998;136(4 Pt 1):632-42.

Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF

Am Heart J. 1998;136(4 Pt 1):632-42.

Am Heart J. 1998;136(4 Pt 1):632-42.

Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF

Am Heart J. 1998;136(4 Pt 1):632-42.

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; 31:1414-9

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;59:1395-400

Clinical Trial

Int J Clin Pract. 2005;59:1395-400

Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation

Int J Clin Pract. 2005;59:1395-400

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; 79:568-75

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≤0.001

++

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

IndicationIndication

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

UsageUsage

Patient Weight

DoseSecond 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.

0.01 mg/kg

( 0.1 ml/kg)

CORVERT product monograph

Dosing Post Cardiac SurgeryDosing Post Cardiac Surgery

Patient Weight

DoseSecond iv Infusion

60 kgiv 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 kgiv infusion over 10 min.0.005 mg/kg ( 0.05 ml/kg)

CORVERT product monograph

Adverse effectsAdverse effects

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

ContraindicationContraindication

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

WarningWarning

Before treatment of ibutilide, hypokalemia and hypomagnesemia should be corrected

Patients should be observed with continous ECG monitoring for at least 4 h

Ibutilide SummaryIbutilide 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