Identification
- Summary
Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib.
- Brand Names
- Zykadia
- Generic Name
- Ceritinib
- DrugBank Accession Number
- DB09063
- Background
Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy. About 4% of patients with NSCLC have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Following treatment with crizotinib (a first-generation ALK inhibitor), most tumours develop drug resistance due to mutations in key "gatekeeper" residues of the enzyme. This occurrence led to development of novel second-generation ALK inhibitors such as ceritinib to overcome crizotinib resistance. The FDA approved ceritinib in April 2014 due to a surprisingly high response rate (56%) towards crizotinib-resistant tumours and has designated it with orphan drug status.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Ceritinib (DB09063)
- Weight
- Average: 558.135
Monoisotopic: 557.22273844 - Chemical Formula
- C28H36ClN5O3S
- Synonyms
- Céritinib
- Ceritinib
- Ceritinibum
- N-{2-[(5-chloro-2-{[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propane-2-sulfonamide
- External IDs
- LDK 378
- LDK-378
- LDK378
- NVP-LDK378-NX
Pharmacology
- Indication
Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Refractory, locally advanced non-small cell lung cancer •••••••••••• Treatment of Refractory, metastatic non-small cell lung cancer •••••••••••• - Contraindications & Blackbox Warnings
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Not Available
- Mechanism of action
Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats.
Target Actions Organism AALK tyrosine kinase receptor antagonistHumans - Absorption
After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours.
- Volume of distribution
The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose.
- Protein binding
Ceritinib is 97% bound to human plasma proteins, independent of drug concentration.
- Metabolism
In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma.
- Route of elimination
Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
- Half-life
The terminal half life is 41 hours.
- Clearance
The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Ceritinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Ceritinib can be increased when combined with Abatacept. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Ceritinib. Abrocitinib The serum concentration of Ceritinib can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Ceritinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of ceritinib, which may increase its serum concentration.
- Avoid St. John's Wort. This herb induces the CYP3A metabolism of ceritinib and may reduce its serum concentration.
- Take with food. Food increases the bioavailability of ceritinib. Taking ceritinib in a fasted state increases the risk of adverse gastrointestinal effects like nausea, vomiting, and abdominal pain.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Zykadia
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zykadia Capsule 150 mg Oral Novartis 2015-04-29 Not applicable Canada 
Zykadia Capsule 150 mg Oral Novartis Europharm Limited 2016-09-08 Not applicable EU 
Zykadia Tablet, film coated 150 mg/1 Oral Novartis Pharmaceuticals Corporation 2019-03-18 Not applicable US 
Zykadia Tablet, film coated 150 mg Oral Novartis Europharm Limited 2020-12-16 Not applicable EU Zykadia Capsule 150 mg Oral Novartis Europharm Limited 2016-09-08 Not applicable EU
Categories
- ATC Codes
- L01ED02 — Ceritinib
- Drug Categories
- Anaplastic lymphoma kinase (ALK) inhibitors
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Bradycardia-Causing Agents
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (weak)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Hyperglycemia-Associated Agents
- Kinase Inhibitor
- Moderate Risk QTc-Prolonging Agents
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Protein Kinase Inhibitors
- QTc Prolonging Agents
- Receptor Protein-Tyrosine Kinases, antagonists & inhibitors
- Sulfur Compounds
- Tyrosine Kinase Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylpiperidines. These are compounds containing a phenylpiperidine skeleton, which consists of a piperidine bound to a phenyl group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Piperidines
- Sub Class
- Phenylpiperidines
- Direct Parent
- Phenylpiperidines
- Alternative Parents
- Benzenesulfonyl compounds / Phenoxy compounds / Phenol ethers / Aniline and substituted anilines / Toluenes / Alkyl aryl ethers / Aminopyrimidines and derivatives / Aralkylamines / Halopyrimidines / Imidolactams show 9 more
- Substituents
- Alkyl aryl ether / Amine / Aminopyrimidine / Aniline or substituted anilines / Aralkylamine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenesulfonyl group show 25 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- K418KG2GET
- CAS number
- 1032900-25-6
- InChI Key
- VERWOWGGCGHDQE-UHFFFAOYSA-N
- InChI
- InChI=1S/C28H36ClN5O3S/c1-17(2)37-25-15-21(20-10-12-30-13-11-20)19(5)14-24(25)33-28-31-16-22(29)27(34-28)32-23-8-6-7-9-26(23)38(35,36)18(3)4/h6-9,14-18,20,30H,10-13H2,1-5H3,(H2,31,32,33,34)
- IUPAC Name
- 5-chloro-N2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
- SMILES
- CC(C)OC1=C(NC2=NC=C(Cl)C(N2)=NC2=CC=CC=C2S(=O)(=O)C(C)C)C=C(C)C(=C1)C1CCNCC1
References
- Synthesis Reference
Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. Pubmed
- General References
- Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. doi: 10.1056/NEJMoa1311107. [Article]
- Nishio M, Murakami H, Horiike A, Takahashi T, Hirai F, Suenaga N, Tajima T, Tokushige K, Ishii M, Boral A, Robson M, Seto T: Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors. J Thorac Oncol. 2015 Jul;10(7):1058-66. doi: 10.1097/JTO.0000000000000566. [Article]
- Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M: Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21. [Article]
- Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. [Article]
- Mano H: The EML4-ALK oncogene: targeting an essential growth driver in human cancer. Proc Jpn Acad Ser B Phys Biol Sci. 2015;91(5):193-201. doi: 10.2183/pjab.91.193. [Article]
- External Links
- KEGG Drug
- D10551
- PubChem Compound
- 57379345
- PubChem Substance
- 310264998
- ChemSpider
- 29315053
- BindingDB
- 50436850
- 1535457
- ChEBI
- 78432
- ChEMBL
- CHEMBL2403108
- ZINC
- ZINC000096272772
- PDBe Ligand
- 4MK
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ceritinib
- PDB Entries
- 4mkc
- FDA label
- Download (307 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Recruiting Treatment ALK Positive Malignancies 1 3 Completed Treatment Non-Small Cell Lung Cancer (NSCLC) 2 3 Recruiting Health Services Research Soft Tissue Sarcoma 1 2 Active Not Recruiting Treatment Non-squamous Non-small-cell Lung Cancer (NSQ NSCLC) / Stage IV Lung Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v8 1 2 Completed Treatment Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 150 mg/1 Tablet, film coated Oral 150 MG Tablet, film coated Oral 150 mg/1 Capsule Oral 150 mg Capsule Oral Capsule Oral 150.00 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8039474 No 2011-10-18 2030-06-29 US US8703787 No 2014-04-22 2032-02-02 US US8377921 No 2013-02-19 2027-11-20 US US8039479 No 2011-10-18 2030-06-29 US US7893074 No 2011-02-22 2026-04-25 US US9309229 No 2016-04-12 2032-01-18 US US7153964 No 2006-12-26 2021-02-26 US US7964592 No 2011-06-21 2027-01-13 US US8399450 No 2013-03-19 2027-11-20 US US8835430 No 2014-09-16 2023-01-31 US US9018204 No 2015-04-28 2023-01-31 US US8188276 No 2012-05-29 2023-01-31 US US9416112 No 2016-08-16 2023-01-31 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source pKa 9.7 and 4.1 FDA Label - Predicted Properties
Property Value Source Water Solubility 0.00222 mg/mL ALOGPS logP 5.23 ALOGPS logP 5.81 Chemaxon logS -5.4 ALOGPS pKa (Strongest Acidic) 11.58 Chemaxon pKa (Strongest Basic) 10.07 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 105.24 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 153.86 m3·mol-1 Chemaxon Polarizability 61.33 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 221.88539 predictedDeepCCS 1.0 (2019) [M+H]+ 224.28096 predictedDeepCCS 1.0 (2019) [M+Na]+ 230.19347 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Transmembrane receptor protein tyrosine kinase activity
- Specific Function
- Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis a...
- Gene Name
- ALK
- Uniprot ID
- Q9UM73
- Uniprot Name
- ALK tyrosine kinase receptor
- Molecular Weight
- 176440.535 Da
References
- Galkin AV, Melnick JS, Kim S, Hood TL, Li N, Li L, Xia G, Steensma R, Chopiuk G, Jiang J, Wan Y, Ding P, Liu Y, Sun F, Schultz PG, Gray NS, Warmuth M: Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5. Epub 2006 Dec 21. [Article]
- Marsilje TH, Pei W, Chen B, Lu W, Uno T, Jin Y, Jiang T, Kim S, Li N, Warmuth M, Sarkisova Y, Sun F, Steffy A, Pferdekamper AC, Li AG, Joseph SB, Kim Y, Liu B, Tuntland T, Cui X, Gray NS, Steensma R, Wan Y, Jiang J, Chopiuk G, Li J, Gordon WP, Richmond W, Johnson K, Chang J, Groessl T, He YQ, Phimister A, Aycinena A, Lee CC, Bursulaya B, Karanewsky DS, Seidel HM, Harris JL, Michellys PY: Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013 Jul 25;56(14):5675-90. doi: 10.1021/jm400402q. Epub 2013 Jun 26. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- 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
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
Drug created at May 11, 2015 22:20 / Updated at February 20, 2024 23:54