Details of the Drug

General Information of Drug (ID: DMI782S)

• Drug Name: Erdafitinib
• Synonyms: 1346242-81-6; UNII-890E37NHMV; 890E37NHMV; Erdafitinib [USAN:INN]; Erdafitinib (USAN/INN); GTPL9039; SCHEMBL2583760; CHEMBL3545376; MolPort-044-560-398; JNJ-42756493 (Erdafitinib); s8401; compound 4 [WO2011135376]; ZINC168520308; AKOS030526429; CS-4988; DB12147; AC-30222; 1,2-Ethanediamine, N1-(3,5-dimethoxyphenyl)-N2-(1-methylethyl)-N1-(3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl)-; HY-18708; AS-35040; KB-333716; D10927; N'-(3,5-dimethoxyphenyl)-N'-[3-(1-methylpyrazol-4-yl)quino

Indication

Disease Entry	ICD 11	Status	REF
Bladder cancer	2C94	Approved	[1]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
Urothelial carcinoma	2C92.0	Phase 2	[3]
Lymphoma	2A80-2A86	Phase 1/2	[4]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 446.5
  Topological Polar Surface Area (xlogp); 3.2
  Rotatable Bond Count (rotbonds); 9
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 7
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 29,268 mcgh/L [5]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1,399 mcg/L [5]
  Clearance: The apparent oral clearance of drug is 0.362 L/h [6]
  Elimination: About 69% of the dose was recovered in feces (19% as unchanged) and 19% in urine (13% as unchanged) [7]
  Half-life: The concentration or amount of drug in body reduced by one-half in 59 hours [6]
  Metabolism: The drug is metabolized via the cytochrome P450 enzym CYP2C9 and CYP3A4 isoenzymes [5]
  Vd: The volume of distribution (Vd) of drug is 26-29 L [6]
• Chemical Identifiers:
  Formula: C25H30N6O2
  IUPAC Name: N'-(3,5-dimethoxyphenyl)-N'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-N-propan-2-ylethane-1,2-diamine
  Canonical SMILES: CC(C)NCCN(C1=CC2=NC(=CN=C2C=C1)C3=CN(N=C3)C)C4=CC(=CC(=C4)OC)OC
  InChI: InChI=1S/C25H30N6O2/c1-17(2)26-8-9-31(20-10-21(32-4)13-22(11-20)33-5)19-6-7-23-24(12-19)29-25(15-27-23)18-14-28-30(3)16-18/h6-7,10-17,26H,8-9H2,1-5H3
  InChIKey: OLAHOMJCDNXHFI-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 67462786
  CAS Number: 1346242-81-6
  DrugBank ID: DB12147
  TTD ID: D0NW0T
  INTEDE ID: DR0595

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Fibroblast growth factor receptor (FGFR)	TT0LF7H	NOUNIPROTAC	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[8]
Cytochrome P450 2C9 (CYP2C9) Main DME	DE5IED8	CP2C9_HUMAN	Substrate	[8]

Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Ivosidenib	DM8S6T7	Moderate	Increased metabolism of Erdafitinib caused by Ivosidenib mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[32]
Oliceridine	DM6MDCF	Moderate	Increased metabolism of Erdafitinib caused by Oliceridine mediated induction of CYP450 enzyme.	Acute pain [MG31]	[32]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Erdafitinib caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[32]
Eslicarbazepine	DMZREFQ	Major	Increased plasma concentrations of Erdafitinib and Eslicarbazepine due to competitive inhibition of the same metabolic pathway.	Epilepsy/seizure [8A61-8A6Z]	[32]
Bay 80-6946	DMLOS5R	Moderate	Increased metabolism of Erdafitinib caused by Bay 80-6946 mediated induction of CYP450 enzyme.	Follicular lymphoma [2A80]	[32]
Rucaparib	DM9PVX8	Moderate	Decreased clearance of Erdafitinib due to the transporter inhibition by Rucaparib.	Ovarian cancer [2C73]	[32]
Betrixaban	DM2C4RF	Moderate	Decreased clearance of Erdafitinib due to the transporter inhibition by Betrixaban.	Venous thromboembolism [BD72]	[32]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [2] ClinicalTrials.gov (NCT03210714) Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial). U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800036975)
• [5] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [6] Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.
• [7] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [8] FDA label of Erdafitinib. The 2020 official website of the U.S. Food and Drug Administration.
• [9] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [10] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [11] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [12] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [13] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [14] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [15] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [16] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [17] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [18] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [19] Tamoxifen inhibits cytochrome P450 2C9 activity in breast cancer patients. J Chemother. 2006 Aug;18(4):421-4.
• [20] Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology. 2003 Aug;144(8):3382-98.
• [21] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [22] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [23] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [24] New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. Curr Drug Metab. 2009 Dec;10(10):1075-126.
• [25] A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res Treat. 2003 Dec;82(3):191-7.
• [26] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [27] Tumor angiogenesis as a therapeutic target. Drug Discov Today. 2001 Oct 1;6(19):1005-1024.
• [28] TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities. Molecular Cancer Therapeutics. 01/2014; 12(11_Supplement):A270-A270.
• [29] The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther. 2014 Nov;13(11):2547-58.
• [30] Preclinical profile of BAY 1163877 - a selective pan-FGFR inhibitor in phase 1 clinical trial. Cancer Research. 10/2014; 74(19 Supplement):1739-1739.
• [31] Clinical pipeline report, company report or official report of InnoCare Pharma.
• [32] Product Information. Balversa (erdafitinib). Janssen Products, LP, Horsham, PA.