Details of the Drug

General Information of Drug (ID: DMMPTLH)

• Drug Name: Entrectinib
• Synonyms: 1108743-60-7; RXDX-101; UNII-L5ORF0AN1I; Entrectinib (RXDX-101); L5ORF0AN1I; Benzamide, N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methyl-1-piperazinyl)-2-[(tetrahydro-2H-pyran-4-yl)amino]-; Benzamide, N-(5-((3,5-difluorophenyl)methyl)-1H-indazol-3-yl)-4-(4-methyl-1-piperazinyl)-2-((tetrahydro-2H-pyran-4-yl)amino)-; Entrectinib [USAN:INN]; YMX; Kinome_2659; Entrectinib(rxdx-101); Entrectinib (USAN/INN); SCHEMBL3512601; GTPL8290; CHEMBL1983268; KS-00000TSK

Indication

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25	Approved	[1]
Colorectal cancer	2B91.Z	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
Mammary analogue secretory carcinoma	2C60	Phase 1	[4]
Neuroblastoma	2D11.2	Phase 1	[2]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 2:
  Molecular Weight (mw); 560.6
  Logarithm of the Partition Coefficient (xlogp); 5.7
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 8
• ADMET Property:
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4-5 h [5]
  Clearance: The clearance of drug is 19.6 L/h [5]
  Elimination: After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine [5]
  Half-life: The concentration or amount of drug in body reduced by one-half in 20 hours [5]
  Metabolism: The drug is metabolized via the CYP3A4 [5]
  Vd: The volume of distribution (Vd) of drug is 551 L [5]
• Chemical Identifiers:
  Formula: C31H34F2N6O2
  IUPAC Name: N-[5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide
  Canonical SMILES: CN1CCN(CC1)C2=CC(=C(C=C2)C(=O)NC3=NNC4=C3C=C(C=C4)CC5=CC(=CC(=C5)F)F)NC6CCOCC6
  InChI: InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
  InChIKey: HAYYBYPASCDWEQ-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 25141092
  CAS Number: 1108743-60-7
  DrugBank ID: DB11986
  TTD ID: D0O0LS
  INTEDE ID: DR0582
  ACDINA ID: D01050
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Inhibitor	[1]
BDNF/NT-3 growth factors receptor (TrkB)	TTKN7QR	NTRK2_HUMAN	Inhibitor	[1]
NT-3 growth factor receptor (TrkC)	TTXABCW	NTRK3_HUMAN	Inhibitor	[1]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Inhibitor	[1]
Tropomyosin-related kinase A (TrkA)	TTTDVOJ	NTRK1_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4) Main DME	DE4LYSA	CP3A4_HUMAN	Substrate	[6]

Molecular Expression Atlas of This Drug

• The Studied Disease: Non-small-cell lung cancer
• ICD Disease Classification: 2C25

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
NT-3 growth factor receptor (TrkC)	DTT	NTRK3	7.06E-04	-0.14	-0.43
Tropomyosin-related kinase A (TrkA)	DTT	NTRK1	8.72E-01	-0.04	-0.22
BDNF/NT-3 growth factors receptor (TrkB)	DTT	NTRK2	3.06E-01	-0.15	-0.31
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 Entrectinib (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Entrectinib and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[7]
Ivosidenib	DM8S6T7	Major	Increased risk of prolong QT interval by the combination of Entrectinib and Ivosidenib.	Acute myeloid leukaemia [2A60]	[8]
Gilteritinib	DMTI0ZO	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Gilteritinib.	Acute myeloid leukaemia [2A60]	[7]
Oliceridine	DM6MDCF	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Oliceridine.	Acute pain [MG31]	[9]
Levalbuterol	DM5YBO1	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Levalbuterol.	Asthma [CA23]	[10]
Troleandomycin	DMUZNIG	Major	Decreased metabolism of Entrectinib caused by Troleandomycin mediated inhibition of CYP450 enzyme.	Bacterial infection [1A00-1C4Z]	[9]
LY2835219	DM93VBZ	Moderate	Decreased metabolism of Entrectinib caused by LY2835219 mediated inhibition of CYP450 enzyme.	Breast cancer [2C60-2C6Y]	[11]
MK-8228	DMOB58Q	Major	Decreased metabolism of Entrectinib caused by MK-8228 mediated inhibition of CYP450 enzyme.	Cytomegaloviral disease [1D82]	[7]
Polatuzumab vedotin	DMF6Y0L	Moderate	Decreased metabolism of Entrectinib caused by Polatuzumab vedotin mediated inhibition of CYP450 enzyme.	Diffuse large B-cell lymphoma [2A81]	[12]
Deutetrabenazine	DMUPFLI	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Deutetrabenazine.	Dystonic disorder [8A02]	[7]
Eslicarbazepine	DMZREFQ	Moderate	Increased metabolism of Entrectinib caused by Eslicarbazepine mediated induction of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[13]
Ripretinib	DM958QB	Moderate	Decreased metabolism of Entrectinib caused by Ripretinib mediated inhibition of CYP450 enzyme.	Gastrointestinal stromal tumour [2B5B]	[7]
Avapritinib	DMK2GZX	Moderate	Decreased metabolism of Entrectinib caused by Avapritinib mediated inhibition of CYP450 enzyme.	Gastrointestinal stromal tumour [2B5B]	[9]
MK-1439	DM215WE	Minor	Decreased metabolism of Entrectinib caused by MK-1439 mediated inhibition of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[14]
Berotralstat	DMWA2DZ	Major	Decreased metabolism of Entrectinib caused by Berotralstat mediated inhibition of CYP450 enzyme.	Innate/adaptive immunodeficiency [4A00]	[9]
Brigatinib	DM7W94S	Moderate	Increased metabolism of Entrectinib caused by Brigatinib mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[13]
PF-06463922	DMKM7EW	Major	Increased metabolism of Entrectinib caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[13]
Selpercatinib	DMZR15V	Major	Increased risk of prolong QT interval by the combination of Entrectinib and Selpercatinib.	Lung cancer [2C25]	[15]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Entrectinib and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[16]
Siponimod	DM2R86O	Major	Increased risk of ventricular arrhythmias by the combination of Entrectinib and Siponimod.	Multiple sclerosis [8A40]	[7]
Ozanimod	DMT6AM2	Major	Increased risk of ventricular arrhythmias by the combination of Entrectinib and Ozanimod.	Multiple sclerosis [8A40]	[17]
Fedratinib	DM4ZBK6	Major	Decreased metabolism of Entrectinib caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[7]
Rucaparib	DM9PVX8	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Rucaparib.	Ovarian cancer [2C73]	[7]
Triclabendazole	DMPWGBR	Moderate	Increased risk of prolong QT interval by the combination of Entrectinib and Triclabendazole.	Parasitic worm infestation [1F90]	[9]
Macimorelin	DMQYJIR	Major	Increased risk of prolong QT interval by the combination of Entrectinib and Macimorelin.	Pituitary gland disorder [5A60-5A61]	[18]
Lefamulin	DME6G97	Major	Increased risk of prolong QT interval by the combination of Entrectinib and Lefamulin.	Pneumonia [CA40]	[19]
Darolutamide	DMV7YFT	Minor	Decreased metabolism of Entrectinib caused by Darolutamide mediated inhibition of CYP450 enzyme.	Prostate cancer [2C82]	[20]
Voxelotor	DMCS6M5	Major	Decreased metabolism of Entrectinib caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[9]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Entrectinib caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[9]
Larotrectinib	DM26CQR	Moderate	Decreased metabolism of Entrectinib caused by Larotrectinib mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[9]

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

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Beta-D-lactose	E00099	6134	Diluent; Dry powder inhaler carrier; Lyophilization aid
Crospovidone	E00626	Not Available	Disintegrant
Hypromellose	E00634	Not Available	Coating agent
Magnesium stearate	E00208	11177	lubricant
Tartaric acid	E00029	875	Acidulant; Complexing agent; Flavoring agent
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
Entrectinib 100 mg capsule	100 mg	Capsule	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT04589845) Tumor-Agnostic Precision Immuno-Oncology and Somatic Targeting Rational for You (TAPISTRY) Platform Study. U.S. National Institutes of Health.
• [4] Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372... Cancer Discov. 2017 Apr;7(4):400-409.
• [5] FDA Approved Drug Productsl: Rozlytrek (entrectinib) capsules for oral use
• [6] Entrectinib: first global approval. Drugs. 2019 Sep;79(13):1477-1483.
• [7] Cerner Multum, Inc. "Australian Product Information.".
• [8] Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
• [9] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [10] Product Information. Arcapta Neohaler (indacaterol). Novartis Pharmaceuticals, East Hanover, NJ.
• [11] Product Information. Verzenio (abemaciclib). Lilly, Eli and Company, Indianapolis, IN.
• [12] Product Information. Polivy (polatuzumab vedotin). Genentech, South San Francisco, CA.
• [13] Product Information. Rozlytrek (entrectinib). Genentech, South San Francisco, CA.
• [14] Product Information. Pifeltro (doravirine). Merck & Company Inc, Whitehouse Station, NJ.
• [15] Product Information. Retevmo (selpercatinib). Lilly, Eli and Company, Indianapolis, IN.
• [16] Al-Nawakil C, Willems L, Mauprivez C, et.al "Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors." Leuk Lymphoma 55 (2014): 1670-4. [PMID: 24090500]
• [17] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.
• [18] Product Information. Macrilen (macimorelin). Aeterna Zentaris, Charleston, SC.
• [19] Product Information. Fareston (toremifene). Schering Laboratories, Kenilworth, NJ.
• [20] Product Information. Nubeqa (darolutamide). Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.