Ixazomib

Identification

Summary

Ixazomib is a monoclonal antibody used with other medications to treat multiple myeloma in patients who have received one other therapy already.

Brand Names
Ninlaro
Generic Name
Ixazomib
DrugBank Accession Number
DB09570
Background

Ixazomib a second generation proteasome inhibitor (PI) and the first oral PI approved by the FDA in November 2015 for multiple myeloma treatment in combination with 2 other therapies (lenalidomide and dexamethasone) for patients who have received at least 1 prior therapy. It was found to have similar efficacy to bortezomib (the first PI approved for multiple myeloma therapy) in the control of myeloma growth and prevention of bone loss. Ixazomib citrate is marketed by Takeda Pharmaceuticals under the brand name Ninlaro, which is a prodrug that becomes quickly converted to its active metabolite, ixazomib, after administration.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 361.03
Monoisotopic: 360.081492
Chemical Formula
C14H19BCl2N2O4
Synonyms
  • Ixazomib
External IDs
  • MLN 2238
  • MLN-2238
  • MLN2238
  • MLN9708

Pharmacology

Indication

Ixazomib is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMultiple myelomaRegimen in combination with: Lenalidomide (DB00480), Dexamethasone (DB01234)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In vitro studies have shown ixazomib to induce apoptosis in multiple myeloma cells sensitive or resistant to other conventional therapies. In mouse xenograft models, ixazomib induced tumor growth inhibition.

Mechanism of action

Ixazomib is an N-capped dipeptidyl leucine boronic acid which reversibly inhibits the CT-L proteolytic (β5) site of the 20S proteasome. At higher concentrations, ixazomib also seems to inhibit the proteolytic β1 and β2 subunits and to induce accumulation of ubiquitinated proteins.

Absorption

After oral administration, the time to reach maximum concentration in plasma was 1 hour. The mean absolute oral bioavailability is 58%.

Volume of distribution

The steady-state volume of distribution is 543 L.

Protein binding

99%

Metabolism

Metabolism of ixazomib is expected to be by CYP and non-CYP pathways, with no predominant CYP isozyme contribution. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (<1%).

Route of elimination

62% in urine and 22% in feces.

Half-life

Terminal half-life is 9.5 days.

Clearance

Not Available

Adverse Effects
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Toxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, hepatitis cholestatic and hepatotoxicity have each been reported in <1% of patients. Ixazomib can cause fetal harm when administered to pregnant women, and therefore it should also be advised to women of reproductive age to avoid becoming pregnant on ixazomib.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Ixazomib which could result in a higher serum level.
AbametapirThe serum concentration of Ixazomib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Ixazomib can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Ixazomib can be decreased when combined with Acalabrutinib.
AceclofenacAceclofenac may decrease the excretion rate of Ixazomib which could result in a higher serum level.
Food Interactions
  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of ixazomib.
  • Take on an empty stomach. Food increases the absorption of ixazomib, take ixazomib dose at least one hour before and at least two hours after food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ixazomib citrate46CWK97Z3K1239908-20-3MBOMYENWWXQSNW-AWEZNQCLSA-N
International/Other Brands
Ninlaro
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NinlaroCapsule3.0 mgOralTakeda Pharma A/S2021-02-10Not applicableEU flag
NinlaroCapsule3 mgOralTakeda2016-09-21Not applicableCanada flag
NinlaroCapsule3 mg/1OralTakeda Pharmaceuticals America, Inc.2015-11-20Not applicableUS flag
NinlaroCapsule3 mg/1OralTakeda Pharmaceuticals America, Inc.2015-11-202023-10-31US flag
NinlaroCapsule2.3 mgOralTakeda Pharma A/S2021-02-10Not applicableEU flag

Categories

ATC Codes
L01XG03 — Ixazomib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as hippuric acids and derivatives. These are compounds containing a hippuric acid or a derivative, with a structure characterized the presence of a benzoyl group linked to the N-terminal of a glycine.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Hippuric acids and derivatives
Alternative Parents
N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / 2-halobenzoic acids and derivatives / 3-halobenzoic acids and derivatives / Benzoyl derivatives / Dichlorobenzenes / Aryl chlorides / Vinylogous halides / Secondary carboxylic acid amides / Boronic acids
show 8 more
Substituents
1,4-dichlorobenzene / 2-halobenzoic acid or derivatives / 3-halobenzoic acid or derivatives / Alkylborane / Alpha-amino acid amide / Alpha-amino acid or derivatives / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzoyl
show 26 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
71050168A2
CAS number
1072833-77-2
InChI Key
MXAYKZJJDUDWDS-LBPRGKRZSA-N
InChI
InChI=1S/C14H19BCl2N2O4/c1-8(2)5-12(15(22)23)19-13(20)7-18-14(21)10-6-9(16)3-4-11(10)17/h3-4,6,8,12,22-23H,5,7H2,1-2H3,(H,18,21)(H,19,20)/t12-/m0/s1
IUPAC Name
[(1R)-1-{2-[(2,5-dichlorophenyl)formamido]acetamido}-3-methylbutyl]boronic acid
SMILES
CC(C)C[C@H](NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl)B(O)O

References

General References
  1. Offidani M, Corvatta L, Caraffa P, Gentili S, Maracci L, Leoni P: An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther. 2014 Sep 29;7:1793-800. doi: 10.2147/OTT.S49187. eCollection 2014. [Article]
  2. Gentile M, Offidani M, Vigna E, Corvatta L, Recchia AG, Morabito L, Morabito F, Gentili S: Ixazomib for the treatment of multiple myeloma. Expert Opin Investig Drugs. 2015;24(9):1287-98. doi: 10.1517/13543784.2015.1065250. Epub 2015 Jul 3. [Article]
KEGG Drug
D10130
PubChem Compound
25183872
PubChem Substance
310265228
ChemSpider
25027391
BindingDB
50398609
RxNav
1723735
ChEBI
90942
ChEMBL
CHEMBL2141296
ZINC
ZINC000169946773
PDBe Ligand
6V8
Drugs.com
Drugs.com Drug Page
Wikipedia
Ixazomib
PDB Entries
5lf7 / 7q11 / 8qyf
FDA label
Download (463 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentMultiple Myeloma (MM)1
4CompletedTreatmentRelapsed/Refractory Multiple Myeloma (RRMM)1
4RecruitingTreatmentMultiple Myeloma (MM)3
4WithdrawnTreatmentMultiple Myeloma (MM)1
3Active Not RecruitingTreatmentAutologous Stem Cell Transplantation / Multiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral2.3 mg/1
CapsuleOral3 mg/1
CapsuleOral3.0 MG
CapsuleOral4 mg/1
CapsuleOral4.0 MG
CapsuleOral2.3 mg
CapsuleOral3 mg
CapsuleOral4 mg
CapsuleOral
Capsule, coatedOral2.3 mg
Capsule, coatedOral3 mg
Capsule, coatedOral4 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8871745No2014-10-282027-08-06US flag
US8530694No2013-09-102027-08-06US flag
US7442830No2008-10-282027-08-06US flag
US9175017No2015-11-032029-06-16US flag
US8003819No2011-08-232027-08-06US flag
US9233115No2016-01-122024-08-12US flag
US8546608No2013-10-012024-08-12US flag
US7687662No2010-03-302027-08-06US flag
US8859504No2014-10-142029-06-16US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0124 mg/mLALOGPS
logP2.06ALOGPS
logP2.57Chemaxon
logS-4.5ALOGPS
pKa (Strongest Acidic)8.64Chemaxon
pKa (Strongest Basic)-1.8Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area98.66 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity84.56 m3·mol-1Chemaxon
Polarizability36.3 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-006t-9513000000-a60e06b004f3a32d02e7
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-0109000000-37d2e0ec7a54c8fccf53
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00e9-6429000000-21742d07bf80b40c26f3
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01q9-9734000000-9792d466abb8acb641ad
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0007-9010000000-02090c242165d907f311
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9000000000-6a5a429211929497b02d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-8951000000-8a88f57be04795ba2209
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Gupta N, Diderichsen PM, Hanley MJ, Berg D, van de Velde H, Harvey RD, Venkatakrishnan K: Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling. Clin Pharmacokinet. 2017 Nov;56(11):1355-1368. doi: 10.1007/s40262-017-0526-4. [Article]
  2. Kumar SK, Buadi FK, LaPlant B, Halvorson A, Leung N, Kapoor P, Dingli D, Gertz MA, Go RS, Bergsagel PL, Lin Y, Dispenzieri A, Hwa YL, Fonder A, Hobbs M, Fonseca R, Hayman SR, Stewart AK, Lust JA, Mikhael J, Gonsalves W, Reeder C, Skacel T, Rajkumar SV, Lacy MQ: Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma. Blood Cancer J. 2018 Jul 30;8(8):70. doi: 10.1038/s41408-018-0106-3. [Article]
  3. Ixazomib FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Ixazomib EMA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. EMA Label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Ixazomib FDA Label [File]

Drug created at November 30, 2015 19:10 / Updated at March 03, 2024 02:16