Identification

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Name
Avapritinib
Accession Number
DB15233
Type
Small Molecule
Groups
Approved, Investigational
Description

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.2,3 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 2020.3

Structure
Thumb
Synonyms
  • Avapritinib
External IDs
70C366 / BLU-285 / C-366 / X-720776 / X720776
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AyvakitTablet, film coated200 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUs
AyvakitTablet, film coated100 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUs
AyvakitTablet, film coated300 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
513P80B4YJ
CAS number
1703793-34-3
Weight
Average: 498.57
Monoisotopic: 498.240419072
Chemical Formula
C26H27FN10
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

Pharmacology

Indication

Avapritinib is indicated for the treatment of unresectable, metastatic gastrointestinal stromal tumors with a platelet-derived growth factor receptor alpha exon 18 mutation.2,3

Associated Conditions
Pharmacodynamics

Avapritinib is a selective kinase inhibitor that negatively modulates the action of cell transporters to resensitize them to other chemotherapies.3 It has a long duration of action as it is given once daily.3 Patients should be counselled regarding the risk of intracranial hemorrhage, CNS effects, and embryo-fetal toxicity.3

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

TargetActionsOrganism
UPlatelet derived growth factor receptor alpha
inhibitor
Humans
UMast/stem cell growth factor receptor Kit
inhibitor
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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.3

Volume of distribution

The mean apparent volume of distribution is 1200L.3

Protein binding

Avapritinib is 98.8% protein bound in serum.3

Metabolism

Avapritinib is metabolized mainly by CYP3A4 and CYP2C9 in vitro.3 A 310mg oral dose is recovered as 49% unchanged drug, 35% hydroxy glucuronide metabolite, and 14% oxidatively deaminated metabolite.3

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.3

Half life

The half life of avapritinib is 32-57h.3

Clearance

The mean apparent oral clearance of avapritinib is 19.5L/h.3

Toxicity

Data regarding overdoses of avapritinib are not readily available.3

Affected organisms
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
(R)-warfarinThe metabolism of Avapritinib can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Avapritinib can be decreased when combined with (S)-Warfarin.
AbataceptThe metabolism of Avapritinib can be increased when combined with Abatacept.
AbirateroneThe metabolism of Avapritinib can be decreased when combined with Abiraterone.
AcenocoumarolThe metabolism of Avapritinib can be decreased when combined with Acenocoumarol.
AcetohexamideThe metabolism of Avapritinib can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazoleThe metabolism of Avapritinib can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acidThe metabolism of Avapritinib can be decreased when combined with Acetylsalicylic acid.
AdalimumabThe metabolism of Avapritinib can be increased when combined with Adalimumab.
AfelimomabThe metabolism of Avapritinib can be increased when combined with Afelimomab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

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. [PubMed:31117741]
  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. [PubMed:31205499]
  3. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
External Links
ChemSpider
58828673
RxNav
2272107
Wikipedia
Avapritinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentGastrointestinal Stromal Tumors (GISTs) / Other Relapsed or Refractory Solid Tumors1
1RecruitingTreatmentMalignant mast cell neoplasm / Relapsed or Refractory Myeloid Malignancies / Systemic mastocytosis with associated hematological neoplasm / Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease1
1, 2RecruitingTreatmentGastrointestinal Stromal Tumors1
2RecruitingTreatmentAdvanced Systemic Mastocytosis / Malignant mast cell neoplasm / Systemic Mastocytosis With an Associated Hematologic Neoplasm / Systemic mastocytosis with associated hematological neoplasm1
2RecruitingTreatmentIndolent Systemic Mastocytosis / Smoldering Systemic Mastocytosis1
3Active Not RecruitingTreatmentGIST1
Not AvailableAvailableNot AvailableGIST1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral300 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0301 mg/mLALOGPS
logP2.68ALOGPS
logP3.26ChemAxon
logS-4.2ALOGPS
pKa (Strongest Basic)8.52ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.29 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity164.55 m3·mol-1ChemAxon
Polarizability52.99 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

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. [PubMed:31117741]
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. [PubMed:31117741]

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
  1. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
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. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Modulator
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
  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. [PubMed:31117741]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Modulator
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
  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. [PubMed:31117741]

Drug created on May 20, 2019 09:02 / Updated on February 02, 2020 03:21