Details of the Drug

General Information of Drug (ID: DMTI0ZO)

• Drug Name: Gilteritinib
• Synonyms: 6-Ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide; ASP 2215; Gilteritinib; Gilteritinib (ASP-2215); Gilteritinib (ASP2215); Gilteritinib (USAN/INN); Gilteritinib [USAN:INN]; Gilteritinib(ASP2215); Xospata

Indication

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Approved	[1]

• Therapeutic Class: Anticancer Agents
• Affected Organisms: Humans
• ATC Code:
  L01EX13: Gilteritinib
  L01EX: Other protein kinase inhibitors
  L01E: PROTEIN KINASE INHIBITORS
  L01: ANTINEOPLASTIC AGENTS
  L: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight; 552.724
  Logarithm of the Partition Coefficient; Not Available
  Rotatable Bond Count; 9
  Hydrogen Bond Donor Count; 3
  Hydrogen Bond Acceptor Count; 10
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 6943 mcgh/L [2]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 374 mcg/L [2]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4-8 h [2]
  Clearance: The clearance of drug is 14.85 L/h [3]
  Elimination: From the administered dose, gilteritinib is mainly excreted in feces which represents 64.5% of the administered dose while 16.4% is recovered in urine either as the unchanged drug or as its metabolites [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 45 - 159 hours [5]
  Metabolism: The drug is metabolized via the liver [4]
  Vd: The volume of distribution (Vd) of drug is 1092 L [3]
• Chemical Identifiers:
  Formula: C29H44N8O3
  IUPAC Name: 6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide
  Canonical SMILES: CCC1=NC(=C(N=C1NC2CCOCC2)NC3=CC(=C(C=C3)N4CCC(CC4)N5CCN(CC5)C)OC)C(=O)N
  InChI: InChI=1S/C29H44N8O3/c1-4-23-28(31-20-9-17-40-18-10-20)34-29(26(33-23)27(30)38)32-21-5-6-24(25(19-21)39-3)37-11-7-22(8-12-37)36-15-13-35(2)14-16-36/h5-6,19-20,22H,4,7-18H2,1-3H3,(H2,30,38)(H2,31,32,34)
  InChIKey: GYQYAJJFPNQOOW-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 49803313
  CAS Number: 1254053-43-4
  UNII: 66D92MGC8M
  DrugBank ID: DB12141
  VARIDT ID: DR00358

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Fms-like tyrosine kinase 3 (FLT-3)	TTGJCWZ	FLT3_HUMAN	Inhibitor	[1]
Tyrosine-protein kinase UFO (AXL)	TTZPY6J	UFO_HUMAN	Inhibitor	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[8]

Molecular Expression Atlas of This Drug

• The Studied Disease: Acute myeloid leukaemia
• ICD Disease Classification: 2A60

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Fms-like tyrosine kinase 3 (FLT-3)	DTT	FLT3	2.11E-01	-0.05	-0.16
P-glycoprotein 1 (ABCB1)	DTP	P-GP	9.39E-02	1.07E-01	2.80E-01
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.04E-02	6.29E-02	3.54E-01

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Gilteritinib

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Ivosidenib	DM8S6T7	Major	Increased risk of prolong QT interval by the combination of Gilteritinib and Ivosidenib.	Acute myeloid leukaemia [2A60]	[9]

Coadministration of a Drug Treating the Disease Different from Gilteritinib (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Gilteritinib and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[10]
Oliceridine	DM6MDCF	Moderate	Increased risk of prolong QT interval by the combination of Gilteritinib and Oliceridine.	Acute pain [MG31]	[11]
Levalbuterol	DM5YBO1	Moderate	Increased risk of prolong QT interval by the combination of Gilteritinib and Levalbuterol.	Asthma [CA23]	[12]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Gilteritinib caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[11]
Pexidartinib	DMS2J0Z	Major	Increased risk of hepatotoxicity by the combination of Gilteritinib and Pexidartinib.	Bone/articular cartilage neoplasm [2F7B]	[13]
Deutetrabenazine	DMUPFLI	Moderate	Increased risk of prolong QT interval by the combination of Gilteritinib and Deutetrabenazine.	Dystonic disorder [8A02]	[14]
Eslicarbazepine	DMZREFQ	Moderate	Increased metabolism of Gilteritinib caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[11]
Tazemetostat	DMWP1BH	Moderate	Increased metabolism of Gilteritinib caused by Tazemetostat mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[11]
Berotralstat	DMWA2DZ	Moderate	Decreased metabolism of Gilteritinib caused by Berotralstat mediated inhibition of CYP450 enzyme.	Innate/adaptive immunodeficiency [4A00]	[15]
Pralsetinib	DMWU0I2	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Pralsetinib.	Lung cancer [2C25]	[10]
Ubrogepant	DM749I3	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[16]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[17]
Siponimod	DM2R86O	Major	Increased risk of ventricular arrhythmias by the combination of Gilteritinib and Siponimod.	Multiple sclerosis [8A40]	[10]
Ozanimod	DMT6AM2	Major	Increased risk of ventricular arrhythmias by the combination of Gilteritinib and Ozanimod.	Multiple sclerosis [8A40]	[18]
Fedratinib	DM4ZBK6	Moderate	Decreased metabolism of Gilteritinib caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[15]
Rucaparib	DM9PVX8	Moderate	Increased risk of prolong QT interval by the combination of Gilteritinib and Rucaparib.	Ovarian cancer [2C73]	[11]
Triclabendazole	DMPWGBR	Moderate	Increased risk of prolong QT interval by the combination of Gilteritinib and Triclabendazole.	Parasitic worm infestation [1F90]	[11]
Macimorelin	DMQYJIR	Major	Increased risk of prolong QT interval by the combination of Gilteritinib and Macimorelin.	Pituitary gland disorder [5A60-5A61]	[19]
Lefamulin	DME6G97	Major	Decreased metabolism of Gilteritinib caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[20]
Darolutamide	DMV7YFT	Minor	Decreased clearance of Gilteritinib due to the transporter inhibition by Darolutamide.	Prostate cancer [2C82]	[21]
Voxelotor	DMCS6M5	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Voxelotor.	Sickle-cell disorder [3A51]	[15]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Gilteritinib caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[15]
Lusutrombopag	DMH6IKO	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Lusutrombopag.	Thrombocytopenia [3B64]	[22]
Betrixaban	DM2C4RF	Moderate	Decreased clearance of Gilteritinib due to the transporter inhibition by Betrixaban.	Venous thromboembolism [BD72]	[23]

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, Shimada I, Mori K, Kuromitsu S: Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565. doi: 10.1007/s10637-017-0470-z. Epub 2017 May 17.
• [3] Clinical trials
• [4] Clinical trials
• [5] American Society of Clinical Oncology
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01665)
• [8] ClinicalTrials.gov (NCT02456883) Study to Investigate the Absorption, Metabolism and Excretion of [14C] ASP2215 in Patients With Advanced Solid Tumors.
• [9] Product Information. Tibsovo (ivosidenib). Agios Pharmaceuticals, Cambridge, MA.
• [10] Cerner Multum, Inc. "Australian Product Information.".
• [11] Product Information. Xospata (gilteritinib). Astellas Pharma US, Inc, Deerfield, IL.
• [12] Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.
• [13] Product Information. Turalio (pexidartinib). Daiichi Sankyo, Inc., Parsippany, NJ.
• [14] Product Information. Austedo (deutetrabenazine). Teva Pharmaceuticals USA, North Wales, PA.
• [15] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [16] Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
• [17] Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
• [18] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.
• [19] Product Information. Macrilen (macimorelin). Aeterna Zentaris, Charleston, SC.
• [20] Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
• [21] Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
• [22] EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".
• [23] Product Information. Bevyxxa (betrixaban). Portola Pharmaceuticals, South San Francisco, CA.