NAV

Quizartinib

Identification

Summary

Quizartinib is a FLT3 inhibitor used in combination with cytarabine and anthracycline to treat acute myeloid leukemia with FLT3 internal tandem duplication

Brand Names
Vanflyta
Generic Name
Quizartinib
DrugBank Accession Number
DB12874
Background

Quizartinib is an oral and potent fms-like tyrosine kinase 3 (FLT3) inhibitor and it is the first drug developed specifically targeting FLT3, as other agents with FLT3 inhibition activities were investigated with other targets in mind.1 Additionally, quizartinib also demonstrates inhibitory activity toward FLT3 with internal tandem duplication (ITD), although with a 10-fold lower affinity compared to wild-type FLT3.4 FLT3-ITD mutation is present in 75% of FLT3-mutated AML, leading to constitutively active FLT3 and thus poorer overall survival and higher risk of relapse.2 Multiple clinical trials have demonstrated quizartinib's efficacy in relapsed/refractory FLT3-ITD mutant AML.3 Therefore, quizartinib is proven to be a beneficial addition to the current AML treatment regimen, although serious side effects such as QT prolongation necessitates further research to optimize quizartinib's addition to AML standard of care.1

Quizartinib was approved by the FDA in July 2023 and developed under the brand name VANFLYTA by Daiichi Sankyo.6 The FDA approval was based on positive results from the QuANTUM-First trial for FLT3-ITD positive AML, where quizartinib combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation, followed by a maintenance monotherapy resulted in a 22% reduction in the risk of death.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
Weight
Average: 560.67
Monoisotopic: 560.220574708
Chemical Formula
C29H32N6O4S
Synonyms
  • N-(5-(1,1-Dimethylethyl)isoxazol-3-yl)-N'-(4-(7-(2-(morpholin-4-yl)ethoxy)imidazo(2,1-b)benzothiazol-2-yl)phenyl)urea
  • Quizartinib
  • Quizartinibum
External IDs
  • AC 010220
  • AC 220
  • AC-010220
  • AC-220
  • AC010220
  • AC220

Pharmacology

Indication

Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test.4

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Quizartinib showed antitumor activity in a mouse model of FLT3-ITD-dependent leukemia. In vitro, studies have shown that quizartinib is a predominant inhibitor of the slow delayed rectifier potassium current, IKs.4

In AML patients receiving quizartinib at a dose of 90 mg/day for females and 135 mg/day for males on a 28-day schedule, the median levels of phospho-FLT3 (pFLT3) and total FLT3 (tFLT3) decreased from 3312 RLU or 5639 RLU respectively at day 1 to 1235 RLU and 142 RLU respectively at day 8. Additionally, pFLT3 levels are statistically significantly higher (p < 0.0001, Mann Whitney test) for the ITD+ subjects on day 1; however, pFLT3 levels was reduced to a similar level in patients with or without the ITD mutation.5

The exposure-response analysis predicted a concentration-dependent QTcF interval median prolongation of 18 and 24 ms [upper bound of 2-sided 90% confidence interval (CI): 21 and 27 ms] at the median steady-state Cmax of quizartinib at the 26.5 mg and 53 mg dose level during maintenance therapy.4

Mechanism of action

Quizartinib is a small molecule inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major active metabolite AC886 bind to the adenosine triphosphate (ATP) binding domain of FLT3 with comparable affinity, and both had 10-fold lower affinity towards FLT3-ITD mutation compared to FLT3 in a binding assay. Quizartinib and AC886 inhibited FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting downstream FLT3 receptor signaling and blocking FLT3-ITD-dependent cell proliferation.4

TargetActionsOrganism
AReceptor-type tyrosine-protein kinase FLT3
inhibitor
Humans
Absorption

The mean (SD) absolute bioavailability of quizartinib from the tablet formulation was 71% (±7%) in healthy subjects. After oral administration under fasted conditions, time to peak concentration (median Tmax) of quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively, in healthy subjects. Following the administration of 35.4 mg quizartinib once daily in patients with newly diagnosed acute myeloid leukemia, the Cmax and AUC0-24h were calculated to be 140 ng/mL (71%) and 2,680 ng.h/mL (85%) respectively during the induction therapy and 204 ng/mL (64%) and 3,930 ng.h/mL (78%) respectively during the consolidation therapy.4 For the metabolite AC886, the Cmax and AUC0-24h were estimated to be 163 ng/mL (52%) and 3,590 ng.h/mL (51%) respectively during the induction therapy and 172 ng/mL (47%) and 3,800 ng.h/mL (46%) respectively during the consolidation therapy.4

Increasing the once daily dose of quizartinib to 53 mg also increases the Cmax and AUC0-24h of quizartinib to 529 ng/mL (60%) and 10,200 ng.h/mL (75%) respectively at steady state. The Cmax and AUC0-24h of the metabolite AC886 also increases to 262 ng/mL (48%) and 5,790 ng•h/mL (46%) respectively.4

No clinically significant differences in the pharmacokinetics of quizartinib were observed when administered with a high-fat, high-calorie meal.4

Volume of distribution

Volume of distribution at steady state in healthy subjects was estimated to be 275 L (17%).4

Protein binding

In vitro plasma protein binding of quizartinib and AC886 is 99% or greater. In vitro blood-to-plasma ratio for quizartinib and AC886 ranges from 0.79-1.30 and 1.36-3.19, respectively.4

Metabolism

In vitro quizartinib is primarily metabolized via oxidation by CYP3A4/5 and AC886 is formed and metabolized by CYP3A4/5.4

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Route of elimination

Following a single radiolabeled dose of quizartinib 53 mg to healthy subjects, 76.3% of the total radioactivity was recovered in feces (4% unchanged) and 1.64% in urine.4

Half-life

The mean (SD) effective half-lives (t1/2) in patients with newly diagnosed AML for quizartinib and AC886 during maintenance therapy are 81 hours (±73) and 136 hours (±113), respectively.4

Clearance

Total body clearance of quizartinib in healthy subjects was estimated to be 2.23 L/hour (29%).4

Adverse Effects
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Toxicity

Based on findings from animal studies and its mechanism of action, quizartinib can cause embryo-fetal harm when administered to a pregnant woman.4

There are no available data on quizartinib use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day (see Data). Advise pregnant women of the potential risk to a fetus.4

Carcinogenicity studies have not been conducted with quizartinib.4

Quizartinib was mutagenic in a bacterial reverse mutation (Ames) assay and not mutagenic in an in vivo transgenic rat mutation assay. Quizartinib was not genotoxic in vitro in mouse lymphoma thymidine kinase mutation and human lymphocyte chromosome aberration assays, or in an in vivo rat bone marrow micronucleus assay.4

Fertility studies in animals have not been conducted with quizartinib. However, adverse findings in male and female reproductive systems were observed in repeat dose toxicity studies in rats and monkeys. Findings in female animals (rats or monkeys) included ovarian cysts, vaginal mucosal modifications, and atrophy of the uterus, ovary, and vagina, starting at exposures (AUC) approximately 0.2 times the MRHD of 53 mg/day. In male animals (rats and monkeys), findings included testicular seminiferous tubular degeneration, failure of sperm release, germ cell depletion in the testes, and oligospermia/aspermia, starting at exposures approximately 0.4 times the MRHD. After approximately one month of recovery period, all these findings except the vaginal mucosal modifications in the female rats were reversible.4

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
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interactions in your software
AbacavirThe metabolism of Abacavir can be decreased when combined with Quizartinib.
AbametapirThe serum concentration of Quizartinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Quizartinib can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Quizartinib.
AbrocitinibThe serum concentration of Quizartinib can be increased when it is combined with Abrocitinib.
AcalabrutinibThe metabolism of Quizartinib can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Quizartinib.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Quizartinib.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Quizartinib.
AdagrasibThe risk or severity of QTc prolongation can be increased when Adagrasib is combined with Quizartinib.
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Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Quizartinib dihydrochlorideWK7Q6ZIZ101132827-21-4DHYPGRVMIOATAE-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VanflytaTablet, film coated17.7 mg/1OralDaiichi Sankyo Inc.2023-07-20Not applicableUS flag
VanflytaTablet, film coated26.5 mg/1OralDaiichi Sankyo Inc.2023-07-20Not applicableUS flag

Categories

ATC Codes
L01EX11 — Quizartinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylimidazoles. These are polycyclic aromatic compounds containing a benzene ring linked to an imidazole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Imidazoles
Direct Parent
Phenylimidazoles
Alternative Parents
N-phenylureas / Benzothiazoles / Alkyl aryl ethers / N-substituted imidazoles / Morpholines / Imidolactams / Thiazoles / Heteroaromatic compounds / Isoxazoles / Ureas
show 8 more
Substituents
1,3-benzothiazole / 4-phenylimidazole / 5-phenylimidazole / Alkyl aryl ether / Amine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
7LA4O6Q0D3
CAS number
950769-58-1
InChI Key
CVWXJKQAOSCOAB-UHFFFAOYSA-N
InChI
InChI=1S/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36)
IUPAC Name
3-(5-tert-butyl-1,2-oxazol-3-yl)-1-(4-{10-[2-(morpholin-4-yl)ethoxy]-7-thia-2,5-diazatricyclo[6.4.0.0²,⁶]dodeca-1(8),3,5,9,11-pentaen-4-yl}phenyl)urea
SMILES
CC(C)(C)C1=CC(NC(=O)NC2=CC=C(C=C2)C2=CN3C(SC4=C3C=CC(OCCN3CCOCC3)=C4)=N2)=NO1

References

General References
  1. Levis M: Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia. Future Oncol. 2014;10(9):1571-9. doi: 10.2217/fon.14.105. [Article]
  2. Garcia-Horton A, Yee KW: Quizartinib for the treatment of acute myeloid leukemia. Expert Opin Pharmacother. 2020 Dec;21(17):2077-2090. doi: 10.1080/14656566.2020.1801637. Epub 2020 Aug 9. [Article]
  3. Zhou F, Ge Z, Chen B: Quizartinib (AC220): a promising option for acute myeloid leukemia. Drug Des Devel Ther. 2019 Apr 8;13:1117-1125. doi: 10.2147/DDDT.S198950. eCollection 2019. [Article]
  4. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
  5. EMA Assessment Report: quizartinib [Link]
  6. VANFLYTA® First FLT3 Inhibitor Approved in the U.S. Specifically for Patients with Newly Diagnosed FLT3-ITD Positive AML [Link]
Human Metabolome Database
HMDB0257064
KEGG Drug
D09955
PubChem Compound
24889392
PubChem Substance
347829030
ChemSpider
24640357
BindingDB
50300690
RxNav
2643048
ChEBI
90217
ChEMBL
CHEMBL576982
ZINC
ZINC000043204002
PDBe Ligand
P30
Wikipedia
Quizartinib
PDB Entries
4rt7 / 4xuf

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Myeloid Leukemia1
3CompletedTreatmentAcute Myeloid Leukemia / Leukemias1
3WithdrawnTreatmentAcute Myeloid Leukemia1
2Active Not RecruitingTreatmentAcute Myeloid Leukemia1
2CompletedTreatmentAcute Myeloid Leukemia3
2TerminatedTreatmentAcute Myeloid Leukemia1
2Unknown StatusTreatmentAcute Myeloid Leukemia / FLT3-ITD Mutation1
2, 3Unknown StatusTreatmentAcute Myeloid Leukemia / Myelodysplastic Syndrome1
1CompletedTreatmentAcute Myeloid Leukemia4
1CompletedTreatmentAcute Myeloid Leukemia, Childhood / Childhood Acute Lymphoblastic Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral17.7 mg/1
Tablet, film coatedOral26.5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9585892No2007-03-162027-03-16US flag
US9555040No2010-05-142030-05-14US flag
US8836218No2010-03-232030-03-23US flag
US8357690No2011-02-262031-02-26US flag
US8129374No2007-03-162027-03-16US flag
US7968543No2009-08-152029-08-15US flag
US8865710No2009-08-152029-08-15US flag
US8883783No2007-03-162027-03-16US flag
US9675549No2013-09-302033-09-30US flag
US8557810No2007-03-162027-03-16US flag
US7820657No2008-09-262028-09-26US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityvery slightly solubleL47426
Predicted Properties
PropertyValueSource
Water Solubility0.0509 mg/mLALOGPS
logP5.13ALOGPS
logP5.16Chemaxon
logS-4ALOGPS
pKa (Strongest Acidic)10.43Chemaxon
pKa (Strongest Basic)6.62Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area106.16 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity168.24 m3·mol-1Chemaxon
Polarizability61.51 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Details1. Receptor-type tyrosine-protein kinase FLT3
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vascular endothelial growth factor-activated receptor activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells...
Gene Name
FLT3
Uniprot ID
P36888
Uniprot Name
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight
112902.51 Da
References
  1. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
No
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: VANFLYTA® (quizartinib) tablets, for oral use [Link]
Details2. Cytochrome P450 3A5
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
Details3. UDP-glucuronosyltransferase 1-1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
References
  1. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
Details4. Cytochrome P450 3A7
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]

Carriers

Details1. Serum albumin
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. EMA Assessment Report: quizartinib [Link]

Transporters

Details1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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. FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
  2. EMA Assessment Report: quizartinib [Link]
Details2. ATP-binding cassette sub-family G member 2
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
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. Bhullar J, Natarajan K, Shukla S, Mathias TJ, Sadowska M, Ambudkar SV, Baer MR: The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. PLoS One. 2013 Aug 14;8(8):e71266. doi: 10.1371/journal.pone.0071266. eCollection 2013. [Article]

Drug created at October 21, 2016 00:57 / Updated at September 24, 2023 02:55