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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Avapritinib (DB15233)

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Weight

Average: 498.57
Monoisotopic: 498.240419072

Chemical Formula

C₂₆H₂₇FN₁₀

Synonyms

• Avapritinib

External IDs

• 70C366
• BLU-285
• C-366
• X-720776
• X720776

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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

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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		••••••••••••	•••••		••••••

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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	inhibitor	Humans
UMast/stem cell growth factor receptor Kit	inhibitor	Humans

Absorption

A 300mg oral dose of avapritinib reaches a C_max of 813ng/mL with a T_max 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

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Toxicity

Data regarding overdoses of avapritinib are not readily available.⁴

Pathways

Not Available

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	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.

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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
Ayvakit	Tablet, film coated	50 mg/1	Oral	Blueprint Medicines Corporation	2020-01-09	Not applicable
Ayvakit	Tablet, film coated	200 mg/1	Oral	Blueprint Medicines Corporation	2020-01-09	Not applicable
Ayvakit	Tablet, film coated	25 mg/1	Oral	Blueprint Medicines Corporation	2020-01-09	Not applicable
Ayvakit	Tablet, film coated	100 mg/1	Oral	Blueprint Medicines Corporation	2020-01-09	Not applicable

Categories

ATC Codes

L01EX18 — Avapritinib

• L01EX — Other protein kinase inhibitors
• L01E — PROTEIN KINASE INHIBITORS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

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

1. 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]
2. 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]
3. EMA Approved Drug Products: AYVAKYT (avapritinib) Oral Tablets [Link]
4. FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use [Link]
5. FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use (March 2023) [Link]
6. FDA Approved Drug Products: AYVAKIT (avapritinib) tablets, for oral use (May 2023) [Link]

External Links

Human Metabolome Database

HMDB0304850

ChemSpider

58828673

BindingDB

469269

RxNav

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
US9994575	No	2018-06-12	2034-10-15
US9944651	No	2018-04-17	2034-10-15
US11827642	No	2014-10-15	2034-10-15

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

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1. Platelet derived growth factor receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

References

1. 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]

Details2. Mast/stem cell growth factor receptor Kit

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

1. 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]

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Drug created at May 20, 2019 15:02 / Updated at May 31, 2023 07:30