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
Structure for Quizartinib (DB12874)
- 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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- Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- 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
Target Actions Organism AReceptor-type tyrosine-protein kinase FLT3 inhibitorHumans - 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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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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir The metabolism of Abacavir can be decreased when combined with Quizartinib. Abametapir The serum concentration of Quizartinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Quizartinib can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Quizartinib. Abrocitinib The serum concentration of Quizartinib can be increased when it is combined with Abrocitinib. Acalabrutinib The metabolism of Quizartinib can be decreased when combined with Acalabrutinib. Acebutolol The risk or severity of QTc prolongation can be increased when Acebutolol is combined with Quizartinib. Acetaminophen The metabolism of Acetaminophen can be decreased when combined with Quizartinib. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Quizartinib. Adagrasib The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Quizartinib. 
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- Take with or without food.
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.- Product Ingredients
Ingredient UNII CAS InChI Key Quizartinib dihydrochloride WK7Q6ZIZ10 1132827-21-4 DHYPGRVMIOATAE-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Vanflyta Tablet, film coated 17.7 mg/1 Oral Daiichi Sankyo Inc. 2023-07-20 Not applicable US 
Vanflyta Tablet, film coated 26.5 mg/1 Oral Daiichi Sankyo Inc. 2023-07-20 Not applicable US
Categories
- ATC Codes
- L01EX11 — Quizartinib
- Drug Categories
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Benzene Derivatives
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A7 Substrates
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Sulfur Compounds
- Thiazoles
- Tyrosine Kinase Inhibitors
- UGT1A1 Inhibitors
- 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
- 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]
- 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]
- 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]
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
- EMA Assessment Report: quizartinib [Link]
- VANFLYTA® First FLT3 Inhibitor Approved in the U.S. Specifically for Patients with Newly Diagnosed FLT3-ITD Positive AML [Link]
- External Links
- Human Metabolome Database
- HMDB0257064
- KEGG Drug
- D09955
- PubChem Compound
- 24889392
- PubChem Substance
- 347829030
- ChemSpider
- 24640357
- BindingDB
- 50300690
- 2643048
- ChEBI
- 90217
- ChEMBL
- CHEMBL576982
- ZINC
- ZINC000043204002
- PDBe Ligand
- P30
- Wikipedia
- Quizartinib
- PDB Entries
- 4rt7 / 4xuf
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Acute Myeloid Leukemia 1 3 Completed Treatment Acute Myeloid Leukemia / Leukemias 1 3 Withdrawn Treatment Acute Myeloid Leukemia 1 2 Active Not Recruiting Treatment Acute Myeloid Leukemia 1 2 Completed Treatment Acute Myeloid Leukemia 3 2 Terminated Treatment Acute Myeloid Leukemia 1 2 Unknown Status Treatment Acute Myeloid Leukemia / FLT3-ITD Mutation 1 2, 3 Unknown Status Treatment Acute Myeloid Leukemia / Myelodysplastic Syndrome 1 1 Completed Treatment Acute Myeloid Leukemia 4 1 Completed Treatment Acute Myeloid Leukemia, Childhood / Childhood Acute Lymphoblastic Leukemia 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 17.7 mg/1 Tablet, film coated Oral 26.5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9585892 No 2007-03-16 2027-03-16 US US9555040 No 2010-05-14 2030-05-14 US US8836218 No 2010-03-23 2030-03-23 US US8357690 No 2011-02-26 2031-02-26 US US8129374 No 2007-03-16 2027-03-16 US US7968543 No 2009-08-15 2029-08-15 US US8865710 No 2009-08-15 2029-08-15 US US8883783 No 2007-03-16 2027-03-16 US US9675549 No 2013-09-30 2033-09-30 US US8557810 No 2007-03-16 2027-03-16 US US7820657 No 2008-09-26 2028-09-26 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility very slightly soluble L47426 - Predicted Properties
Property Value Source Water Solubility 0.0509 mg/mL ALOGPS logP 5.13 ALOGPS logP 5.16 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 10.43 Chemaxon pKa (Strongest Basic) 6.62 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 106.16 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 168.24 m3·mol-1 Chemaxon Polarizability 61.51 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes 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 Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- 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
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
Enzymes
- 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
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
- 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
- FDA Approved Drug Products: VANFLYTA® (quizartinib) tablets, for oral use [Link]
Carriers
- 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
- EMA Assessment Report: quizartinib [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- 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
- 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
- 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