Details of the Drug

General Information of Drug (ID: DM26CQR)

• Drug Name: Larotrectinib
• Synonyms: UNII-PF9462I9HX; PF9462I9HX; ARRY 470; Larotrectinib [USAN:INN]; GTPL8909; SCHEMBL2241012; NYNZQNWKBKUAII-KBXCAEBGSA-N; BDBM136597; ZINC118399834; AKOS027338709; example 14 [US8865698 B2]; CS-5722; HY-12866; AS-35231; J3.628.138C; US8865698, 14; ARRY470; ARRY-470

Indication

Disease Entry	ICD 11	Status	REF
Solid tumour/cancer	2A00-2F9Z	Approved	[1]

• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 428.4
  Topological Polar Surface Area (xlogp); 1.7
  Rotatable Bond Count (rotbonds); 3
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 7
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 4351 mcgh/L [2]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 788 mcg/L [2]
  Bioavailability: The bioavailability of drug is 34% [2]
  Clearance: The clearance of drug is 98 L/h [3]
  Elimination: Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 2.9 hours [2]
  Metabolism: The drug is metabolized via the CYP3A4 isoenzymes [2]
  Vd: The volume of distribution (Vd) of drug is 48 L [3]
• Chemical Identifiers:
  Formula: C21H22F2N6O2
  IUPAC Name: (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide
  Canonical SMILES: C1C[C@@H](N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CC[C@@H](C4)O)C5=C(C=CC(=C5)F)F
  InChI: InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1
  InChIKey: NYNZQNWKBKUAII-KBXCAEBGSA-N
• Cross-matching ID:
  PubChem CID: 46188928
  CAS Number: 1223403-58-4
  DrugBank ID: DB14723
  TTD ID: D07TOK
  ACDINA ID: D01197

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
BDNF/NT-3 growth factors receptor (TrkB)	TTKN7QR	NTRK2_HUMAN	Inhibitor	[4]
NT-3 growth factor receptor (TrkC)	TTXABCW	NTRK3_HUMAN	Inhibitor	[4]
Tropomyosin-related kinase A (TrkA)	TTTDVOJ	NTRK1_HUMAN	Inhibitor	[4], [5]

Molecular Expression Atlas of This Drug

• The Studied Disease: Solid tumour/cancer
• ICD Disease Classification: 2A00-2F9Z

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

Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Increased risk of hepatotoxicity by the combination of Larotrectinib and Remdesivir.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[15]
Oliceridine	DM6MDCF	Moderate	Decreased metabolism of Larotrectinib caused by Oliceridine mediated inhibition of CYP450 enzyme.	Acute pain [MG31]	[15]
Ripretinib	DM958QB	Moderate	Decreased metabolism of Larotrectinib caused by Ripretinib mediated inhibition of CYP450 enzyme.	Gastrointestinal stromal tumour [2B5B]	[15]
Avapritinib	DMK2GZX	Moderate	Decreased metabolism of Larotrectinib caused by Avapritinib mediated inhibition of CYP450 enzyme.	Gastrointestinal stromal tumour [2B5B]	[16]
Pemigatinib	DM819JF	Moderate	Decreased metabolism of Larotrectinib caused by Pemigatinib mediated inhibition of CYP450 enzyme.	Liver cancer [2C12]	[17]
Pralsetinib	DMWU0I2	Moderate	Decreased metabolism of Larotrectinib caused by Pralsetinib mediated inhibition of CYP450 enzyme.	Lung cancer [2C25]	[18]
Selpercatinib	DMZR15V	Moderate	Decreased clearance of Larotrectinib due to the transporter inhibition by Selpercatinib.	Lung cancer [2C25]	[15]
Calaspargase pegol	DMQZBXI	Moderate	Increased risk of hepatotoxicity by the combination of Larotrectinib and Calaspargase pegol.	Malignant haematopoietic neoplasm [2B33]	[19]
Ubrogepant	DM749I3	Moderate	Decreased metabolism of Larotrectinib caused by Ubrogepant mediated inhibition of CYP450 enzyme.	Migraine [8A80]	[20]
Upadacitinib	DM32B5U	Moderate	Decreased metabolism of Larotrectinib caused by Upadacitinib mediated inhibition of CYP450 enzyme.	Rheumatoid arthritis [FA20]	[15]
Voxelotor	DMCS6M5	Moderate	Decreased metabolism of Larotrectinib caused by Voxelotor mediated inhibition of CYP450 enzyme.	Sickle-cell disorder [3A51]	[15]

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

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Kyselina citronova	E00014	311	Acidulant; Antioxidant; Buffering agent; Complexing agent; Flavoring agent
methylparaben	E00149	7456	Antimicrobial preservative
Gelatin	E00630	Not Available	Other agent
Glycerin	E00026	753	Antimicrobial preservative; Emollient; Flavoring agent; Humectant; Lubricant; Plasticizing agent; Solvent; Suppository base; Tonicity agent; Viscosity-controlling agent
Potassium sorbate	E00566	23676745	Antimicrobial preservative
Propylene glycol	E00040	1030	Antimicrobial preservative; Humectant; Plasticizing agent; Solvent
Saccharose	E00091	5988	Binding agent; Coating agent; Cryoprotectant; Diluent; Flavoring agent; Suspending agent; Viscosity-controlling agent
Sodium citrate dihydrate	E00369	71474	Alkalizing agent; Buffering agent; Complexing agent; Emulsifying agent
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Water	E00035	962	Solvent
Sorbitan tristearate	E00516	17800859	Dispersing agent; Emulsifying agent; Solubilizing agent; Surfactant; Suspending agent; Vaccine adjuvant
Trisodium Phosphate	E00284	24243	Other agent
Hydroxypropyl betadex	E00697	Not Available	Complexing agent; Modified-release agent; penetration agent; Solubilizing agent; Tonicity agent

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Larotrectinib 20 mg/ml solution	20 mg/ml	Solution	Oral
Larotrectinib 100 mg capsule	100 mg	Capsule	Oral
Larotrectinib 25 mg capsule	25 mg	Capsule	Oral

Jump to Detail Pharmaceutical Formulation Page of This Drug

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] 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.
• [3] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [4] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [7] Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol. 2013; 7: 1275-1285.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis. Acta Derm Venereol. 2015 May;95(5):542-8.
• [10] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [11] National Cancer Institute Drug Dictionary (drug id 747694).
• [12] National Cancer Institute Drug Dictionary (drug id 766123).
• [13] MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Res. 2010 Feb 15;70(4):1524-33.
• [14] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.
• [15] Cerner Multum, Inc. "Australian Product Information.".
• [16] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [17] Product Information. Accolate (zafirlukast). Zeneca Pharmaceuticals, Wilmington, DE.
• [18] Product Information. Gavreto (pralsetinib). Blueprint Medicines Corporation, Cambridge, MA.
• [19] 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]
• [20] Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.