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.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

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
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 unresectable, metastatic gastrointestinal stromal tumors with a platelet-derived growth factor receptor alpha exon 18 mutation.2,3

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.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
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

Adverse Effects
Adverseeffects
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Toxicity

Data regarding overdoses of avapritinib are not readily available.3

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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Avapritinib.
AbametapirThe serum concentration of Avapritinib can be increased when it is combined with Abametapir.
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 Acenocoumarol can be decreased when combined with Avapritinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Avapritinib.
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.
Interactions
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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

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AyvakitTablet, film coated300 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUS flag
AyvakitTablet, film coated50 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUS flag
AyvakitTablet, film coated200 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUS flag
AyvakitTablet, film coated25 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUS flag
AyvakitTablet, film coated100 mg/1OralBlueprint Medicines Corporation2020-01-09Not applicableUS flag
AyvakytTablet, film coated100 mgOralBlueprint Medicines (Netherlands) B.V.2020-12-16Not applicableEU flag
AyvakytTablet, film coated300 mgOralBlueprint Medicines (Netherlands) B.V.2020-12-16Not applicableEU flag
AyvakytTablet, film coated200 mgOralBlueprint Medicines (Netherlands) B.V.2020-12-16Not applicableEU flag

Categories

Drug Categories
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. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
ChemSpider
58828673
BindingDB
469269
RxNav
2272107
ChEMBL
CHEMBL4204794
Wikipedia
Avapritinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentGastrointestinal Stromal Tumor (GIST)1
3Active Not RecruitingTreatmentGastrointestinal Stromal Tumor (GIST) / GIST1
2Active Not RecruitingTreatmentAdvanced Systemic Mastocytosis (AdvSM) / Malignant mast cell neoplasm / Systemic Mastocytosis With an Associated Hematologic Neoplasm / Systemic mastocytosis with associated hematological neoplasm1
2RecruitingTreatmentAnatomic Stage IV Breast Cancer AJCC v8 / Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 / Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 / Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 / Locally Advanced Malignant Solid Neoplasm / Locally Advanced Melanoma / Locally Advanced Primary Malignant Central Nervous System Neoplasm / Locally Advanced Sarcoma / Metastatic Malignant Solid Neoplasm / Metastatic Melanoma / Metastatic Primary Malignant Central Nervous System Neoplasm / Metastatic Sarcoma / Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 / Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 / Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 / Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8 / Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 / Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8 / Prognostic Stage IIIC Breast Cancer AJCC v8 / Prognostic Stage IV Breast Cancer AJCC v8 / Stage IIIC Colorectal Cancer AJCC v8 / Stage IIIC Lung Cancer AJCC v8 / Stage IV Colorectal Cancer AJCC v8 / Stage IV Lung Cancer AJCC v8 / Stage IVA Colorectal Cancer AJCC v8 / Stage IVA Lung Cancer AJCC v8 / Stage IVB Colorectal Cancer AJCC v8 / Stage IVB Lung Cancer AJCC v8 / Stage IVC Colorectal Cancer AJCC v81
2RecruitingTreatmentIndolent Systemic Mastocytosis1
1Active Not RecruitingTreatmentMalignant mast cell neoplasm / Relapsed or Refractory Myeloid Malignancies / Systemic mastocytosis with associated hematological neoplasm / Systemic Mastocytosis-associated Hematologic Non-mast Cell Disease1
1CompletedTreatmentGastrointestinal Stromal Tumor (GIST) / Other Relapsed or Refractory Solid Tumors1
1Not Yet RecruitingOtherGastrointestinal Stromal Tumor (GIST) / GIST1
1RecruitingBasic ScienceSoft Tissue Sarcoma, Adult1
1, 2Active Not RecruitingTreatmentGastrointestinal Stromal Tumor (GIST)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral300 mg/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral100 MG
Tablet, film coatedOral200 MG
Tablet, film coatedOral300 MG
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9200002No2015-12-012034-10-15US flag
US9994575No2018-06-122034-10-15US flag
US9944651No2018-04-172034-10-15US flag

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

Targets

Drugtargets2
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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]
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]

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
Inhibitor
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. [Article]
  2. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
  3. Clinical Trials: NCT03465722 Study Protocol [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
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. [Article]
  2. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
  3. 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
  1. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
  2. Clinical Trials: NCT03465722 Study Protocol [Link]
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
  1. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
  2. Clinical Trials: NCT03465722 Study Protocol [Link]
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
  1. FDA Approved Drug Products: Avapritinib Oral Tablets [Link]
  2. Clinical Trials: NCT03465722 Study Protocol [Link]

Drug created on May 20, 2019 15:02 / Updated on August 22, 2021 03:36