Ribociclib

Identification

Summary

Ribociclib is a kinase inhibitor used to treat HR+, HER2- advanced or metastatic breast cancer.

Brand Names
Kisqali 200 Mg Daily Dose Carton, Kisqali Femara Co-pack
Generic Name
Ribociclib
DrugBank Accession Number
DB11730
Background

Ribociclib is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. Ribociclib was approved by the U.S. FDA in March, 2017 as Kisqali.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 434.548
Monoisotopic: 434.254257618
Chemical Formula
C23H30N8O
Synonyms
  • Ribociclib
External IDs
  • LEE-011
  • LEE-011A
  • LEE011
  • LEE011A

Pharmacology

Indication

Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may provide protection against oncogenic processes in specific tissue types. For example, CDK4 is not required for normal mammary tissue development based on knockout mouse studies, but it is needed for growth of Ras-induced mammary tumors, suggesting a potential therapeutic window for treatment with lower toxicity. Ribociclib was reported to be a most selective CDK4/6 inhibitor and to have dose dependent antitumor activity in a number of preclinical models. It inhibited growth of tumor cells by arresting the cells at the G1 checkpoint, which prevents the tumor cells from proliferating.

TargetActionsOrganism
ACyclin-dependent kinase 4
antagonist
inhibitor
Humans
ACyclin-dependent kinase 6
antagonist
inhibitor
Humans
Absorption

Ribociclib is orally bioavailable, highly selective inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. Following oral dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 5 hours. Plasma concentrations increased approximately 2- to 3-fold from Cycle 1 Day 1 to Cycle 1 Day 18/21 due to accumulation, with steady state reached by approximately Day 8 on the basis of trough concentrations after repeated daily dosing. Dose-proportionality analyses demonstrated that exposure to ribociclib increased with dose, with both Cmax and area under the curve (AUC) increasing slightly more than proportional to dose, over the dose range 50–1,200 mg/day

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

32.6 hours

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

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
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be decreased when combined with Ribociclib.
AbametapirThe serum concentration of Ribociclib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Ribociclib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Ribociclib.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Ribociclib.
AcalabrutinibThe metabolism of Acalabrutinib can be decreased when combined with Ribociclib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Ribociclib.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Ribociclib.
AcetazolamideThe metabolism of Ribociclib can be decreased when combined with Acetazolamide.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Ribociclib.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of ribociclib.
  • Avoid St. John's Wort. This herb induces CYP3A metabolism, which may reduce serum levels of ribociclib.
  • Take at the same time every day. Official labeling suggests taking ribociclib in the morning.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ribociclib hydrochloride63YF7YKW7E1211443-80-9JZRSIQPIKASMEV-UHFFFAOYSA-N
Ribociclib succinateBG7HLX29191374639-75-4NHANOMFABJQAAH-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mg/1OralNovartis Pharmaceuticals Corporation2017-03-13Not applicableUS flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet200 mgOralNovartis2018-04-27Not applicableCanada flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
KisqaliTablet, film coated200 mgOralNovartis Europharm Limited2020-12-16Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Kisqali Femara Co-packRibociclib succinate (200 mg/1) + Letrozole (2.5 mg/1)OralNovartis Pharmaceuticals Corporation2017-05-04Not applicableUS flag
Kisqali Femara Co-packRibociclib succinate (200 mg/1) + Letrozole (2.5 mg/1)OralNovartis Pharmaceuticals Corporation2017-05-04Not applicableUS flag
Kisqali Femara Co-packRibociclib succinate (200 mg/1) + Letrozole (2.5 mg/1)OralNovartis Pharmaceuticals Corporation2017-05-04Not applicableUS flag

Categories

ATC Codes
L01XE42 — Ribociclib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyridinylpiperazines. These are compounds containing a pyridinylpiperazine skeleton, which consists of a pyridine linked (not fused) to a piperazine by a bond by a single bond that is not part of a ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Pyridinylpiperazines
Alternative Parents
N-arylpiperazines / Pyrrolo[2,3-d]pyrimidines / Pyrimidinecarboxamides / 2-heteroaryl carboxamides / Pyrrole carboxamides / Dialkylarylamines / Aminopyridines and derivatives / Aminopyrimidines and derivatives / Substituted pyrroles / Imidolactams
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Substituents
2-heteroaryl carboxamide / Amine / Amino acid or derivatives / Aminopyridine / Aminopyrimidine / Aromatic heteropolycyclic compound / Azacycle / Carboxamide group / Carboxylic acid derivative / Dialkylarylamine
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
TK8ERE8P56
CAS number
1211441-98-3
InChI Key
RHXHGRAEPCAFML-UHFFFAOYSA-N
InChI
InChI=1S/C23H30N8O/c1-29(2)22(32)19-13-16-14-26-23(28-21(16)31(19)17-5-3-4-6-17)27-20-8-7-18(15-25-20)30-11-9-24-10-12-30/h7-8,13-15,17,24H,3-6,9-12H2,1-2H3,(H,25,26,27,28)
IUPAC Name
7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
SMILES
CN(C)C(=O)C1=CC2=CN=C(NC3=CC=C(C=N3)N3CCNCC3)N=C2N1C1CCCC1

References

General References
  1. Yu Q, Sicinska E, Geng Y, Ahnstrom M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stal O, Sicinski P: Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006 Jan;9(1):23-32. [Article]
  2. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. [Article]
  3. Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, Shapiro GI: A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2016 Dec 1;22(23):5696-5705. Epub 2016 Aug 19. [Article]
  4. PDF Article- Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer [Link]
  5. FDA approval [Link]
KEGG Drug
D10883
PubChem Compound
44631912
PubChem Substance
347828089
ChemSpider
30798107
BindingDB
148264
RxNav
1873916
ChEMBL
CHEMBL3545110
ZINC
ZINC000072316335
PharmGKB
PA166153470
PDBe Ligand
6ZZ
Wikipedia
Ribociclib
PDB Entries
5l2t

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAdvanced Breast Cancer1
3Active Not RecruitingTreatmentAdvanced, Metastatic Breast Cancer2
3Active Not RecruitingTreatmentBreast Cancer2
3Active Not RecruitingTreatmentBreast Cancer / HER 2 Negative Breast Cancer / Hormone Receptor Positive Tumor1
3Active Not RecruitingTreatmentEarly Breast Cancer1
3CompletedTreatmentAdvanced, Metastatic Breast Cancer1
3RecruitingTreatmentFemale Breast Neoplasms1
3RecruitingTreatmentMalignant Neoplasm of Female Breast1
3RecruitingTreatmentMetastatic Breast Cancer1
3TerminatedOtherBreast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral200 mg
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral200 mg
Tablet, coatedOral200 mg
Tablet, film coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8685980No2014-04-012030-05-25US flag
US9193732No2015-11-242031-11-09US flag
US8415355No2013-04-092031-02-19US flag
US8324225No2012-12-042028-06-17US flag
US9416136No2016-08-162029-08-20US flag
US8962630No2015-02-242029-12-09US flag
US9868739No2018-01-162031-11-09US flag
US10799506No2020-10-132036-04-14US flag

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.231 mg/mLALOGPS
logP2.5ALOGPS
logP2.38ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)11.59ChemAxon
pKa (Strongest Basic)8.87ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area91.21 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity125.59 m3·mol-1ChemAxon
Polarizability49.13 Å3ChemAxon
Number of Rings5ChemAxon
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 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

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase regulator activity
Specific Function
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S tra...
Gene Name
CDK4
Uniprot ID
P11802
Uniprot Name
Cyclin-dependent kinase 4
Molecular Weight
33729.55 Da
References
  1. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during int...
Gene Name
CDK6
Uniprot ID
Q00534
Uniprot Name
Cyclin-dependent kinase 6
Molecular Weight
36938.025 Da
References
  1. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM: Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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. Sorf A, Hofman J, Kucera R, Staud F, Ceckova M: Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro. Biochem Pharmacol. 2018 Aug;154:10-17. doi: 10.1016/j.bcp.2018.04.013. Epub 2018 Apr 16. [Article]

Drug created on October 20, 2016 20:43 / Updated on October 24, 2021 16:00