LAROTRECTINIB SULFATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H22F2N6O2.H2O4S
Molecular Weight	526.514
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

OS(O)(=O)=O.O[C@H]1CCN(C1)C(=O)NC2=C3N=C(C=CN3N=C2)N4CCC[C@@H]4C5=C(F)C=CC(F)=C5

InChI

InChIKey=PXHANKVTFWSDSG-QLOBERJESA-N

InChI=1S/C21H22F2N6O2.H2O4S/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;1-5(2,3)4/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31);(H2,1,2,3,4)/t14-,18+;/m0./s1

HIDE SMILES / InChI

Molecular Formula	C21H22F2N6O2
Molecular Weight	428.4352
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	0
Optical Activity	UNSPECIFIED

Molecular Formula	H2O4S
Molecular Weight	98.078
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Larotrectinib (previously known as ARRY-470 and LOXO-101) is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Larotrectinib is in phase II clinical trials for the treatment patients with solid tumors, non-Hodgkin lymphoma and for the pediatric patients with advanced solid or primary CNS tumors.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Nerve growth factor receptor Trk-A 15	Inhibitor 8,504	20.0 nM [IC50]
Neurotrophic tyrosine kinase receptor type 2 14	Inhibitor 8,504	20.0 nM [IC50]
NT-3 growth factor receptor 9	Inhibitor 8,504	20.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 147	Primary	Approved 8,583	VITRAKVI
Central nervous system neoplasms 4	Primary	Phase II 1,147	Unknown
Non-Hodgkin's lymphoma 81	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
788 ng/mL	100 mg 2 times / day steady-state, oral		LAROTRECTINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
4351 ng × h/mL	100 mg 2 times / day steady-state, oral		LAROTRECTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.9 h	100 mg single, oral		LAROTRECTINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Other AEs: Fatigue, Pyrexia...
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Other AEs: ALT increased, AST increased...
100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years	Disc. AE: Brain edema, Intestinal perforation... Other AEs: Fatigue, Nausea...
150 mg 2 times / day steady, oral Higher than recommended	unhealthy, adult	DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased...
200 mg 2 times / day steady, oral Highest studied dose	unhealthy, adult	DLT: Dizziness...

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AEs

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AE	Significance	Dose	Population
Nasal congestion	all grades, 10%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Decreased appetite	all grades, 11%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Back pain	all grades, 12%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Pain in extremity	all grades, 12%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years
Abdominal pain	all grades, 13%	100 mg 2 times / day steady, oral Recommended	unhealthy, 28 - 82 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1,087 inhibitor 2,252 substrate 1,946	inhibitor 2,438	inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 BSEP 550 CYP1A2 2,153 CYP2B6 926 CYP2C19 2,057 CYP2C8 1,057 MATE1 415 MATE2 267 OAT1 725 OAT3 747 OATP1B1 1,079 OATP1B3 961 OCT1 620 OCT2 779 P-gp 1,741	BCRP 697 OAT1 395 OAT3 391 OATP1B1 503 OATP1B3 435 OCT1 393 OCT2 434 P-gp 2,052	CYP1A2 832 CYP2B6 669

Drug as perpetrator

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Target	Modality	Activity
BCRP 985	inhibitor 4,027	no
BSEP 554	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2B6 1,160	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity
OAT1 395	substrate 4,014	no
OAT3 391	substrate 4,014	no
OATP1B1 503	substrate 4,014	no
OATP1B3 435	substrate 4,014	no
OCT1 393	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA00171P	https://www.aablocks.com/goods/Goods/detail?id=AA00171P
Aaron Chemicals	AR0017TH	http://www.aaronchem.com/1223403-58-4
abcr GmbH	AB463081	http://www.abcr.com/shop/en/AB463081
AbMole Bioscience	M6151	http://www.abmole.com/products/loxo-101.html
Acorn PharmaTech	ACN-043424	http://www.acornpharmatech.com/

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PubMed

PubMed

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Title	Date	PubMed
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.	2015 Oct	26216294
Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6-NTRK3 Fusion.	2018 Jun	29233640

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Sample Use Guides

In Vivo Use Guide

Oral capsule of LOXO-101 (ARRY-470 (FREE BASE)) - 100mg BID

Route of Administration: Oral

In Vitro Use Guide

ARRY-470 is a selective kinase inhibitor with nanomolar activity against TRKA/B/C but no other significant kinase inhibition below 1000nM. Treatment of cells expressing MPRIP- or CD74-NTRK1 with ARRY-470, CEP-701 and, to a lesser extent, crizotinib, inhibited autophosphorylation of RIP-TRKA and CD74-TRKA. It induces cell-cycle arrest in G1 and apoptosis of KM12 cells.

Substance Class	Chemical
Record UNII	RDF76R62ID
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ARRY-470 SULFATE

Preferred Name

English

LAROTRECTINIB SULFATE

Official Name

English

VITRAKVI

Brand Name

English

LAROTRECTINIB SULFATE [USAN]

Common Name

English

1-PYRROLIDINECARBOXAMIDE, N-(5-((2R)-2-(2,5-DIFLUOROPHENYL)-1-PYRROLIDINYL)PYRAZOLO(1,5-A)PYRIMIDIN-3-YL)-3-HYDROXY-, (3S)-, SULFATE (1:1)

Systematic Name

English

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Classification Tree

Code System

Code

Positive

EU-Orphan Drug

EU/3/15/1606

Designated

FDA ORPHAN DRUG

490115

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Code System

Code

Type

Description

SMS_ID

100000177552

PRIMARY

NCI_THESAURUS

C156895

PRIMARY

DRUG BANK

DBSALT002820

PRIMARY

RXCUI

2104548

PRIMARY

FDA UNII

RDF76R62ID

PRIMARY

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Related Record

Type

Details


					PF9462I9HX

LAROTRECTINIB

PARENT -> SALT/SOLVATE

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Related Record

Type

Details


					PF9462I9HX

LAROTRECTINIB

ACTIVE MOIETY

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Sample Use Guides

C_max

T_1/2

Drug as perpetrator