Details of the Drug

General Information of Drug (ID: DM6QOVN)

• Drug Name: HKI-272
• Synonyms: Neratinib (ERBB2 inhibitor)

Indication

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[1]

• Therapeutic Class: Anticancer Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 2:
  Molecular Weight (mw); 557
  Logarithm of the Partition Coefficient (xlogp); 4.9
  Rotatable Bond Count (rotbonds); 11
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 8
• ADMET Property:
  Clearance: The total clearance of drug is 216 L/h []
  Elimination: 97.1% of the total dose is excreted in the feces and 1.13% in the urine []
  Half-life: The concentration or amount of drug in body reduced by one-half in 7 - 17 hours []
  Metabolism: The drug is metabolized via the CYP3A4 []
  Vd: The volume of distribution (Vd) of drug is 6433 L []
• Chemical Identifiers:
  Formula: C30H29ClN6O3
  IUPAC Name: (E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
  Canonical SMILES: CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=CC(=C(C=C3)OCC4=CC=CC=N4)Cl)C#N)NC(=O)/C=C/CN(C)C
  InChI: InChI=1S/C30H29ClN6O3/c1-4-39-28-16-25-23(15-26(28)36-29(38)9-7-13-37(2)3)30(20(17-32)18-34-25)35-21-10-11-27(24(31)14-21)40-19-22-8-5-6-12-33-22/h5-12,14-16,18H,4,13,19H2,1-3H3,(H,34,35)(H,36,38)/b9-7+
  InChIKey: JWNPDZNEKVCWMY-VQHVLOKHSA-N
• Cross-matching ID:
  PubChem CID: 9915743
  ChEBI ID: CHEBI:61397
  CAS Number: 698387-09-6
  DrugBank ID: DB11828
  TTD ID: D0Q9CY
  INTEDE ID: DR1887
  ACDINA ID: D00463

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[2]
ERBB2 messenger RNA (HER2 mRNA)	TTR5TV4	ERBB2_HUMAN	Inhibitor	[3]
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[4]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[2]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[5]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Gene/Protein Processing	[6]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Gene/Protein Processing	[7]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Gene/Protein Processing	[8]

Molecular Expression Atlas of This Drug

• The Studied Disease: Breast cancer
• ICD Disease Classification: 2C60-2C65

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Vascular endothelial growth factor receptor 2 (KDR)	DTT	KDR	1.98E-01	0.11	0.2
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 Disease Different from HKI-272 (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Arn-509	DMT81LZ	Major	Increased metabolism of HKI-272 caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[9]
Gilteritinib	DMTI0ZO	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Gilteritinib.	Acute myeloid leukaemia [2A60]	[10]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of HKI-272 caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[11]
MK-8228	DMOB58Q	Major	Decreased metabolism of HKI-272 caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[11]
Ripretinib	DM958QB	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Ripretinib.	Gastrointestinal stromal tumour [2B5B]	[9]
Berotralstat	DMWA2DZ	Major	Decreased clearance of HKI-272 due to the transporter inhibition by Berotralstat.	Innate/adaptive immunodeficiency [4A00]	[12]
PF-06463922	DMKM7EW	Major	Increased metabolism of HKI-272 caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[9]
IPI-145	DMWA24P	Major	Decreased metabolism of HKI-272 caused by IPI-145 mediated inhibition of CYP450 enzyme.	Mature B-cell leukaemia [2A82]	[11]
Arry-162	DM1P6FR	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Arry-162.	Melanoma [2C30]	[9]
Ubrogepant	DM749I3	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[13]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[14]
Fedratinib	DM4ZBK6	Major	Decreased metabolism of HKI-272 caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[11]
Lefamulin	DME6G97	Moderate	Decreased metabolism of HKI-272 caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[15]
Relugolix	DMK7IWL	Major	Decreased clearance of HKI-272 due to the transporter inhibition by Relugolix.	Prostate cancer [2C82]	[16]
Voxelotor	DMCS6M5	Major	Decreased metabolism of HKI-272 caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[11]
Lusutrombopag	DMH6IKO	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Lusutrombopag.	Thrombocytopenia [3B64]	[17]
Betrixaban	DM2C4RF	Moderate	Decreased clearance of HKI-272 due to the transporter inhibition by Betrixaban.	Venous thromboembolism [BD72]	[18]

Drug Inactive Ingredient(s) (DIG) and Formulation(s) of This Drug

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Crospovidone	E00626	Not Available	Disintegrant
Eisenoxyd	E00585	56841934	Colorant
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 4000	E00654	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Polyvinyl alcohol	E00666	Not Available	Coating agent; Emulsion stabilizing agent; Film/Membrane-forming agent
Povidone	E00667	Not Available	Binding agent; Coating agent; Disintegrant; Film/membrane-forming agent; Solubilizing agent; Suspending agent
Silicon dioxide	E00670	Not Available	Anticaking agent; Opacifying agent; Viscosity-controlling agent
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Water	E00035	962	Solvent
Haematite red	E00236	14833	Colorant
Hydrophobic colloidal silica	E00285	24261	Anticaking agent; Emulsion stabilizing agent; Glidant; Suspending agent; Viscosity-controlling agent
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Neratinib 40 mg tablet	40 mg	Oral Tablet	Oral
Neratinib Maleate 40 mg tablet	40 mg	Tablet	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021154)
• [2] Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cyst... Bioorg Med Chem. 2007 Jun 1;15(11):3635-48.
• [3] Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41.
• [4] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [5] Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 2016 Aug;12(8):947-57.
• [6] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [7] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [8] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [9] Cerner Multum, Inc. "Australian Product Information.".
• [10] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [11] Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D "Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects." Br J Clin Pharmacol 71 (2011): 522-7. [PMID: 21395644]
• [12] Product Information. Orladeyo (berotralstat). BioCryst Pharmaceuticals Inc, Durham, NC.
• [13] Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
• [14] Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
• [15] Product Information. Xenleta (lefamulin). Nabriva Therapeutics US, Inc., King of Prussia, PA.
• [16] Product Information. Orgovyx (relugolix). Myovant Sciences, Inc., Brisbane, CA.
• [17] EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".
• [18] Product Information. Bevyxxa (betrixaban). Portola Pharmaceuticals, South San Francisco, CA.