Identification

Name
Ivabradine
Accession Number
DB09083
Type
Small Molecule
Groups
Approved
Description

Ivabradine is a novel heart rate lowering medicine for the symptomatic management of stable angina pectoralis and symptomatic chronic heart failure. Ivabradine, brand name Corlanor, was approved by the FDA in April 2015 for the treatment of chronic heart failure in patients with an ejection fraction of ≤35%, in sinus rhythm with resting heart rate ≥70 beats per minute, who are not on beta-blockers due to contraindications or already receiving maximum beta-blocker dose. Ivabradine acts by selectively inhibiting the "funny" channel pacemaker current (If) in the sinoatrial node in a dose-dependent fashion, resulting in a lower heart rate and thus more blood to flow to the myocardium. Although non-dihydropyridine calcium channel blockers and beta blockers also effectively lower heart rate, they exhibit adverse events due to their negative ionotropic effects. Therefore, as ivabradine is designed as a "pure" heart rate-lowering drug by selectively acting on the If channels, it may offer a more favorable side effect profile due to its lower likelihood of causing serious adverse effects.

Structure
Thumb
Synonyms
  • 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
  • Ivabradin
  • Ivabradina
  • Ivabradine
  • Ivabradinum
External IDs
S 16257
Product Ingredients
IngredientUNIICASInChI Key
Ivabradine hydrochlorideTP19837BZK148849-67-6HLUKNZUABFFNQS-ZMBIFBSDSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CorlanorTablet, film coated5 mg/1OralAMGEN INC2015-04-20Not applicableUs
CorlanorTablet, film coated7.5 mg/1OralAMGEN INC2015-04-20Not applicableUs
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2005-10-25Not applicableEu
International/Other Brands
Bradia (Biocon) / Ivabid
Categories
UNII
3H48L0LPZQ
CAS number
155974-00-8
Weight
Average: 468.594
Monoisotopic: 468.262422267
Chemical Formula
C27H36N2O5
InChI Key
ACRHBAYQBXXRTO-OAQYLSRUSA-N
InChI
InChI=1S/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1
IUPAC Name
3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
SMILES
COC1=C(OC)C=C2[C@@H](CN(C)CCCN3CCC4=CC(OC)=C(OC)C=C4CC3=O)CC2=C1

Pharmacology

Indication

Ivabradine's indication by the FDA is to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

Associated Conditions
Pharmacodynamics

The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect.

Mechanism of action

Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes.

TargetActionsOrganism
UPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
inhibitor
Human
Absorption

It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivabradine's oral bioavailability is about 40%.

Volume of distribution

~100 L.

Protein binding

70% bound to plasma proteins.

Metabolism

Ivabradine is extensively metabolized by oxidation in the gut and liver by cytochrome P450 3A4 enzyme. Its active metabolite, N-desmethylated derivative, is also metabolized by CYP 3A4. Ivabradine's affinity for CYP 3A4 is low, making it unlikely to affect the metabolism of other drugs; however potent inhibitors or inducers of CYP 3A4 may affect ivabradine's plasma concentration and pharmacodynamic effects and should not be co-administered.

Route of elimination

Metabolites are equally excreted in feces and urine.

Half life

2 hours.

Clearance

Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine.

Toxicity

Ivabradine may cause fetal toxicity when administered to pregnant women. Animal studies in pregnant rats have shown embryo-fetal toxicity and cardiac teratogenic effects. Effective contraception in women is recommended while using ivabradine.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Ivabradine can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Ivabradine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Ivabradine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Ivabradine.
5-androstenedioneThe metabolism of Ivabradine can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Ivabradine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Ivabradine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Ivabradine.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Ivabradine.
AbexinostatThe risk or severity of QTc prolongation can be increased when Abexinostat is combined with Ivabradine.
Food Interactions
  • Grapefruit juice may increase ivabradine exposure by twofold (due to its inhibition of CYP3A4). Therefore grapefruit juice consumption is not recommended while taking ivabradine.

References

General References
  1. DiFrancesco D: The role of the funny current in pacemaker activity. Circ Res. 2010 Feb 19;106(3):434-46. doi: 10.1161/CIRCRESAHA.109.208041. [PubMed:20167941]
  2. Sulfi S, Timmis AD: Ivabradine -- the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006 Feb;60(2):222-8. [PubMed:16451297]
  3. DiFrancesco D, Camm JA: Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. [PubMed:15301560]
  4. Nawarskas JJ, Bowman BN, Anderson JR: Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease. Cardiol Rev. 2015 Jul-Aug;23(4):201-11. doi: 10.1097/CRD.0000000000000070. [PubMed:25839989]
  5. Rosa GM, Ferrero S, Ghione P, Valbusa A, Brunelli C: An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol. 2014 Feb;10(2):279-91. doi: 10.1517/17425255.2014.876005. Epub 2013 Dec 31. [PubMed:24377458]
  6. hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes [Link]
External Links
KEGG Drug
D07165
PubChem Compound
132999
PubChem Substance
310265010
ChemSpider
117373
BindingDB
50326992
ChEBI
85966
ChEMBL
CHEMBL471737
PharmGKB
PA166123415
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ivabradine
ATC Codes
C01EB17 — Ivabradine
AHFS Codes
  • 24:04.92 — Miscellaneous Cardiac Drugs
FDA label
Download (1.45 MB)
MSDS
Download (23.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Individuals1
1, 2RecruitingTreatmentDecompensated Heart Failure1
2CompletedNot AvailableCongestive Heart Failure (CHF)1
2RecruitingTreatmentAngina Pectoris1
2RecruitingTreatmentAutonomic Nervous System Imbalance / Cancer Survivorship / Malignant Lymphomas1
2Unknown StatusTreatmentMultiple Organ Dysfunction Syndrome1
2Unknown StatusTreatmentPostural Tachycardia Syndrome1
2WithdrawnTreatmentDiastolic Heart Failure1
3CompletedNot AvailableAngina Pectoris1
3CompletedTreatmentChronic Heart Failure (CHF)1
3CompletedTreatmentCoronary Artery Disease1
3CompletedTreatmentCoronary Heart Disease (CHD) / Ventricular Dysfunction, Left1
3CompletedTreatmentHeart Failure, Unspecified1
3CompletedTreatmentInappropriate Sinus Tachycardia1
3CompletedTreatmentMitral Valve Stenosis1
3RecruitingTreatmentAging / Healthy Volunteers / Vascular Stiffness1
3RecruitingTreatmentDiabetic Kidney Disease1
3RecruitingTreatmentHeart Diseases / Nonvalvular Atrial Fibrillation1
3RecruitingTreatmentPostural Orthostatic Tachycardia Syndrome (POTS)1
3WithdrawnSupportive CareHeart Transplantation, Elevated Resting Heart Rate1
4Active Not RecruitingTreatmentHeart Failure, Unspecified1
4CompletedTreatmentAsthma, Chronic Obstructive Pulmonary Disease (COPD)1
4CompletedTreatmentCardiac Failure1
4CompletedTreatmentCoronary Artery Disease1
4CompletedTreatmentHeart Failure, Unspecified1
4Not Yet RecruitingTreatmentShock, Cardiogenic1
4Not Yet RecruitingTreatmentChronic heart failure with reduced ejection fraction (NYHA Class IV)1
4RecruitingBasic ScienceDilated Cardiomyopathies, Idiopathic / Electrical Remodeling / Heart Failure, Systolic / Ventricular Remodelling1
4RecruitingTreatmentCardiac Allograft Vasculopathy / Transplanted Heart Complication1
4RecruitingTreatmentHeart Failure, Unspecified2
4RecruitingTreatmentHeart Failure, Unspecified / Shock, Cardiogenic / Tachycardia1
4Unknown StatusDiagnosticCoronary Arteriosclerosis / Coronary Artery Disease1
4Unknown StatusDiagnosticCoronary Artery Disease1
4Unknown StatusTreatmentAcute Coronary Syndromes (ACS)1
4Unknown StatusTreatmentAnginal Pain / Coronary Heart Disease (CHD) / Hemodialysis Treatment1
4Unknown StatusTreatmentHeart Failure, Unspecified2
4Unknown StatusTreatmentHigh Heart Rate1
4WithdrawnBasic ScienceBlood Pressures1
4WithdrawnBasic ScienceCentral Arterial Pressure1
4WithdrawnTreatmentAnginal Pain / Coronary Artery Disease1
Not AvailableActive Not RecruitingTreatmentDecompensated Heart Failure / Heart Failure With Reduced Ejection Fraction (HFrEF)1
Not AvailableCompletedNot AvailableCardiac Failure With Sinus Rhythm or Atrial Fibrillation / Heart Failure, Unspecified / Nonvalvular Atrial Fibrillation1
Not AvailableCompletedNot AvailableChronic Heart Failure (CHF)1
Not AvailableCompletedNot AvailableHeart Failure, Unspecified1
Not AvailableCompletedTreatmentChronic Liver Diseases (CLD) / Diastolic Dysfunction1
Not AvailableCompletedTreatmentCoronary Artery Disease1
Not AvailableNot Yet RecruitingPreventionCardiotoxicity / Chemotherapy Effect / Heart Failure, Unspecified / Neoplasms / Oncology1
Not AvailableRecruitingTreatmentChronic Heart Failure (CHF)1
Not AvailableUnknown StatusTreatmentChronic Heart Failure (CHF) / Nonvalvular Atrial Fibrillation / Sinus Arrhythmia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral5 mg/1
Tablet, film coatedOral7.5 mg/1
Tablet, film coatedOral5 mg
Tablet, film coatedOral7.5 mg
TabletOral5 mg
TabletOral7.5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7879842No2011-02-012026-02-22Us
US7361650No2008-04-222026-04-14Us
US7867996No2011-01-112026-02-22Us
US7361649No2008-04-222026-04-17Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0202 mg/mLALOGPS
logP3.17ALOGPS
logP2.72ChemAxon
logS-4.4ALOGPS
pKa (Strongest Basic)9.37ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area60.47 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity133.51 m3·mol-1ChemAxon
Polarizability54.56 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzazepines. These are organic compounds containing a benzene ring fused to an azepine ring (unsaturated seven-membered heterocycle with one nitrogen atom replacing a carbon atom).
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzazepines
Sub Class
Not Available
Direct Parent
Benzazepines
Alternative Parents
Anisoles / Azepines / Aralkylamines / Alkyl aryl ethers / Tertiary carboxylic acid amides / Trialkylamines / Lactams / Amino acids and derivatives / Azacyclic compounds / Organopnictogen compounds
show 3 more
Substituents
Benzazepine / Anisole / Alkyl aryl ether / Azepine / Aralkylamine / Benzenoid / Tertiary carboxylic acid amide / Carboxamide group / Amino acid or derivatives / Tertiary aliphatic amine
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, aromatic ether, benzazepine, carbobicyclic compound (CHEBI:85966)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated sodium channel activity
Specific Function
Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transpor...
Gene Name
HCN2
Uniprot ID
Q9UL51
Uniprot Name
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Molecular Weight
96949.43 Da
References
  1. hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Rosa GM, Ferrero S, Ghione P, Valbusa A, Brunelli C: An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol. 2014 Feb;10(2):279-91. doi: 10.1517/17425255.2014.876005. Epub 2013 Dec 31. [PubMed:24377458]

Drug created on September 14, 2015 09:24 / Updated on December 12, 2018 07:20