Avapritinib
Identification
- Summary
Avapritinib is a selective tyrosine kinase inhibitor being investigated for the treatment of multidrug resistant gastrointestinal tumors.
- Brand Names
- Ayvakit
- Generic Name
- Avapritinib
- DrugBank Accession Number
- DB15233
- Background
Avapritinib, or BLU-285,1 is a selective tyrosine kinase inhibitor of KIT and platelet derived growth factor receptor alpha indicated for the treatment of unresectable, metastatic gastrointestinal stromal tumors and advanced systemic mastocytosis.2,4 It is one of the first medications available for the treatment of multidrug resistant cancers.1 Avapritinib shares a similar mechanism with ripretinib.
Avapritinib was granted FDA approval on 9 January 2020 4 and EMA approval on 24 September 2020.3
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 498.57
Monoisotopic: 498.240419072 - Chemical Formula
- C26H27FN10
- Synonyms
- Avapritinib
- External IDs
- 70C366
- BLU-285
- C-366
- X-720776
- X720776
Pharmacology
- Indication
Avapritinib is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.4,5
It is also used to treat adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia. However, it is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 X 109 L.4,5
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 Advanced systemic mastocytosis (advsm) •••••••••••• ••••• •••••• Treatment of Aggressive systemic mastocytosis •••••••••••• ••••• •••••• Treatment of Indolent systemic mastocytosis •••••••••••• ••••• •••••• Treatment of Mast cell leukemia (mcl) •••••••••••• ••••• •••••• Treatment of Metastatic gastrointestinal stromal tumor •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies.4 It has a long duration of action as it is given once daily.4 Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, and embryo-fetal toxicity.4
- Mechanism of action
Avapritinib has a negative modulating effect on the transporters ABCB1 and ABCG2, which mediate the multidrug resistance phenotype of some cancers.1 This modulation may be due to interactions of avapritinib with the drug binding pocket of these transporters.1 Negative modulation of these transporters, resensitizes cancerous cells to treatment with chemotherapeutic agents like paclitaxel.1
Target Actions Organism UPlatelet derived growth factor receptor alpha inhibitorHumans UMast/stem cell growth factor receptor Kit inhibitorHumans - Absorption
A 300mg oral dose of avapritinib reaches a Cmax of 813ng/mL with a Tmax of 2.0-4.1h and an AUC of 15400h*ng/mL.4
- Volume of distribution
The mean apparent volume of distribution is 1200L.4
- Protein binding
Avapritinib is 98.8% protein bound in serum.4
- Metabolism
Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro.4 A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite.4
- Route of elimination
Avapritinib is 70% eliminated in the feces with 11% as the unchanged drug and 18% eliminated in the urine with 0.23% as the unchanged drug.4
- Half-life
The half life of avapritinib is 32-57h.4
- Clearance
The mean apparent oral clearance of avapritinib is 19.5L/h.4
- 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
Data regarding overdoses of avapritinib are not readily available.4
- 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 Avapritinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Avapritinib can be increased when combined with Abatacept. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Avapritinib. Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Avapritinib. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Avapritinib. - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of avapritinib.
- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of avapritinib.
- Take on an empty stomach. Take more than 1 hour before or 2 hours after a meal.
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.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ayvakit Tablet, film coated 300 mg/1 Oral Blueprint Medicines Corporation 2020-01-09 Not applicable US Ayvakit Tablet, film coated 50 mg/1 Oral Blueprint Medicines Corporation 2020-01-09 Not applicable US Ayvakit Tablet, film coated 200 mg/1 Oral Blueprint Medicines Corporation 2020-01-09 Not applicable US Ayvakit Tablet, film coated 25 mg/1 Oral Blueprint Medicines Corporation 2020-01-09 Not applicable US Ayvakit Tablet, film coated 100 mg/1 Oral Blueprint Medicines Corporation 2020-01-09 Not applicable US
Categories
- ATC Codes
- L01EX18 — Avapritinib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Bile Salt Export Pump Inhibitors
- BSEP/ABCB11 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- MATE 1 Inhibitors
- MATE 2 Inhibitors
- MATE 2-K Inhibitors
- MATE inhibitors
- P-glycoprotein inhibitors
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 513P80B4YJ
- CAS number
- 1703793-34-3
- InChI Key
- DWYRIWUZIJHQKQ-SANMLTNESA-N
- InChI
- InChI=1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1
- IUPAC Name
- (1S)-1-(4-fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl}pyrimidin-5-yl)ethan-1-amine
- SMILES
- CN1C=C(C=N1)C1=CN2N=CN=C(N3CCN(CC3)C3=NC=C(C=N3)[C@@](C)(N)C3=CC=C(F)C=C3)C2=C1
References
- General References
- Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV: Avapritinib: A Selective Inhibitor of KIT and PDGFRalpha that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. [Article]
- Mazzocca A, Napolitano A, Silletta M, Spalato Ceruso M, Santini D, Tonini G, Vincenzi B: New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019 May 17;11:1758835919841946. doi: 10.1177/1758835919841946. eCollection 2019. [Article]
- EMA Approved Drug Products: AYVAKYT (avapritinib) Oral Tablets [Link]
- FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use [Link]
- FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use (March 2023) [Link]
- FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use (May 2023) [Link]
- External Links
- Human Metabolome Database
- HMDB0304850
- ChemSpider
- 58828673
- BindingDB
- 469269
- 2272107
- ChEMBL
- CHEMBL4204794
- PDBe Ligand
- 9JI
- Wikipedia
- Avapritinib
- PDB Entries
- 8pq9 / 8pqg / 8pqh
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 Active Not Recruiting Treatment Gastrointestinal Stromal Tumor (GIST) 1 3 Completed Treatment Gastrointestinal Stromal Tumor (GIST) 1 2 Active Not Recruiting Treatment Advanced Systemic Mastocytosis (AdvSM) / Aggressive Systemic Mastocytosis / Mast Cell Leukemia (MCL) / Systemic Mastocytosis With an Associated Hematological Neoplasm 1 2 Active Not Recruiting Treatment Indolent Systemic Mastocytosis 1 2 Recruiting Treatment Acute Myeloid Leukemia / Acute Myeloid Leukemia, Childhood 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 200 mg/1 Tablet, film coated Oral 25 mg/1 Tablet, film coated Oral 300 mg/1 Tablet, film coated Oral 50 mg/1 Tablet, film coated Oral 100 MG Tablet, film coated Oral 200 MG Tablet, film coated Oral 25 mg Tablet, film coated Oral 300 MG Tablet, film coated Oral 50 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9200002 No 2015-12-01 2034-10-15 US US9994575 No 2018-06-12 2034-10-15 US US9944651 No 2018-04-17 2034-10-15 US US11827642 No 2014-10-15 2034-10-15 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0301 mg/mL ALOGPS logP 2.68 ALOGPS logP 3.26 Chemaxon logS -4.2 ALOGPS pKa (Strongest Basic) 8.52 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 106.29 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 164.55 m3·mol-1 Chemaxon Polarizability 52.99 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000t-0000900000-1323ed98854a5da69561 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-0000900000-b70ae44fe077265d1dfa Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0000900000-540df92b5ac1dd17427b Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-01ba-0000900000-71aaf9ddb3c3f651fa8b Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-0120900000-2dff9f4650134247bc25 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0296-2545900000-c2618e7fd3aa79301773 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
References
- Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV: Avapritinib: A Selective Inhibitor of KIT and PDGFRalpha that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Transmembrane receptor protein tyrosine kinase activity
- Specific Function
- Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell main...
- Gene Name
- KIT
- Uniprot ID
- P10721
- Uniprot Name
- Mast/stem cell growth factor receptor Kit
- Molecular Weight
- 109863.655 Da
References
- Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV: Avapritinib: A Selective Inhibitor of KIT and PDGFRalpha that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. [Article]
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
References
- FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
- FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorModulator
- 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
References
- Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV: Avapritinib: A Selective Inhibitor of KIT and PDGFRalpha that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. [Article]
- FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
- Clinical Trials: NCT03465722 Study Protocol [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorModulator
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- Wu CP, Lusvarghi S, Wang JC, Hsiao SH, Huang YH, Hung TH, Ambudkar SV: Avapritinib: A Selective Inhibitor of KIT and PDGFRalpha that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines. Mol Pharm. 2019 Jul 1;16(7):3040-3052. doi: 10.1021/acs.molpharmaceut.9b00274. Epub 2019 Jun 4. [Article]
- FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
- Clinical Trials: NCT03465722 Study Protocol [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Transporter activity
- Specific Function
- Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Drug transmembrane transporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
Drug created at May 20, 2019 15:02 / Updated at May 31, 2023 07:30