Find Larotrectinib manufacturers, exporters & distributors on PharmaCompass

Virtual Booth

ACCESS ALL DATA
Browse all information
CHEMISTRY
Discover Molecule Insights

ACTIVE PHARMA INGREDIENTS

8 API Suppliers, 8 Listed Suppliers, $ API Reference Price

8 API Suppliers
8 Listed Suppliers
$ API Reference Price

DEVELOPMENTS

3 Drugs in Development

3 Drugs in Development

INTERMEDIATES

8 Intermediates Suppliers

8 Intermediates Suppliers

FINISHED DOSAGE FORMULATIONS

15 FDF Dossiers, 3 Europe, 12 Australia

15 FDF Dossiers
3 Europe
12 Australia

DIGITAL CONTENT

1 STOCK RECAP #PipelineProspector, 68 NEWS #PharmaBuzz

media
1 STOCK RECAP #PipelineProspector
68 NEWS #PharmaBuzz

GLOBAL SALES INFORMATION

1 US Medicaid Prescriptions, 3 Finished Drug Prices

globalSalesInformation
1 US Medicaid Prescriptions
3 Finished Drug Prices

MARKET PLACE

1 APIs

marketPlace
1 APIs

Synopsis

ACTIVE PHARMA INGREDIENTS

API Suppliers

USDMF

CEP/COS

JDMF

EU WC

KDMF

NDC API

VMF

Listed Suppliers

API REF. PRICE (USD/KG)

MARKET PLACE

API

FDF

FINISHED DOSAGE FORMULATIONS

FDF Dossiers

FDA Orange Book

Europe

Canada

Australia

South Africa

Listed Dossiers

DRUG PRODUCT COMPOSITIONS

REF. STANDARDS OR IMPURITIES

EDQM

USP

Others

PATENTS & EXCLUSIVITIES

US Patents

US Exclusivities

Health Canada Patents

DIGITAL CONTENT

Data Compilation #PharmaFlow

Stock Recap #PipelineProspector

Weekly News Recap #Phispers

News #PharmaBuzz

GLOBAL SALES INFORMATION

US Medicaid (USD)

22,001,911

Annual Reports (USD Million)

Finished Drug Prices

0RELATED EXCIPIENT COMPANIES

0EXCIPIENTS BY APPLICATIONS

Chemistry

Click the arrow to open the dropdown

Click the button for full data set

Also known as: Loxo-101, 1223403-58-4, Arry-470, (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, Vitrakvi, Loxo 101

Molecular Formula

C₂₁H₂₂F₂N₆O₂

Molecular Weight

428.4 g/mol

InChI Key

NYNZQNWKBKUAII-KBXCAEBGSA-N

FDA UNII

PF9462I9HX

Larotrectinib is an orally available, tropomyosin receptor kinase (Trk) inhibitor, with potential antineoplastic activity. Upon administration, larotrectinib binds to Trk, thereby preventing neurotrophin-Trk interaction and Trk activation, which results in both the induction of cellular apoptosis and the inhibition of cell growth in tumors that overexpress Trk. Trk, a receptor tyrosine kinase activated by neurotrophins, is mutated in a variety of cancer cell types and plays an important role in tumor cell growth and survival.

Larotrectinib is a Kinase Inhibitor. The mechanism of action of larotrectinib is as a Tropomyosin Receptor Kinases Inhibitor.

1 2D Structure

Larotrectinib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide

2.1.2 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

2.1.3 InChI Key

NYNZQNWKBKUAII-KBXCAEBGSA-N

2.1.4 Canonical SMILES

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F

2.1.5 Isomeric 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

2.2 Other Identifiers

2.2.1 UNII

PF9462I9HX

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (3s)-n-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

2. Arry-470

3. Arry470

4. Bay-2757556

5. Bay2757556

6. Loxo-101

7. Loxo101

8. N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

9. Vitrakvi

2.3.2 Depositor-Supplied Synonyms

1. Loxo-101

2. 1223403-58-4

3. Arry-470

4. (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

5. Vitrakvi

6. Loxo 101

7. Bay2757556

8. Bay-2757556

9. Loxo101

10. Pf9462i9hx

11. (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide

12. 1-pyrrolidinecarboxamide, N-(5-((2r)-2-(2,5-difluorophenyl)-1-pyrrolidinyl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxy-, (3s)-

13. Arry 470

14. 1-pyrrolidinecarboxamide, N-[5-[(2r)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxy-, (3s)-

15. Larotrectinib [inn]

16. Larotrectinib [mi]

17. Arry-470; Larotrectinib

18. Larotrectinib (usan/inn)

19. Larotrectinib [usan:inn]

20. Larotrectinib [usan]

21. Unii-pf9462i9hx

22. Arry470

23. Larotrectinib [who-dd]

24. Amy264

25. Gtpl8909

26. Schembl2241012

27. Chembl3889654

28. Bdbm136597

29. Dtxsid101020707

30. Bcp16262

31. Ex-a1981

32. Mfcd28902192

33. Nsc785570

34. Nsc801004

35. S5860

36. Larotrectinib (loxo-101 Free Base)

37. Example 14 [us8865698 B2]

38. Zinc118399834

39. Cs-5722

40. Db14723

41. Nsc-785570

42. Nsc-801004

43. Ac-33660

44. As-35231

45. Hy-12866

46. J3.628.138c

47. D11137

48. Us8865698, 14

49. Q27081513

50. Arry-470;arry 470 : Loxo-101; Loxo101; Larotrectinib

51. Arry470;arry-470;arry 470;loxo 101;loxo101;larotrectinib

52. (3s)-n-(5-((2r)-2-(2,5-difluorophenyl)pyrrolidin- 1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide

53. (3s)-n-(5-((2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide

54. (s)-n-(5 -((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

55. (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin -1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

56. (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide

57. (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3 Yl)-3-hydroxypyrrolidine-1-carboxamide

2.4 Create Date

2010-07-06

3 Chemical and Physical Properties

Molecular Formula	C₂₁H₂₂F₂N₆O₂
Molecular Weight	428.4 g/mol
XLogP3	1.7
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	3
Exact Mass	428.17723029 g/mol
Monoisotopic Mass	428.17723029 g/mol
Topological Polar Surface Area	86 Å²
Heavy Atom Count	31
Formal Charge	0
Complexity	659
Isotope Atom Count	0
Defined Atom Stereocenter Count	2
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Larotrectinib is a tyrosine kinase inhibitor that is currently indicated for the treatment of adult and pediatric patients with solid tumors that either a) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, b) are metastatic or where surgical resection is likely to result in severe morbidity, and c) have no satisfactory alternative treatments or that have progressed following treatment. At the moment, these uses of larotrectinib are only approved under the auspices of an accelerated approval by the US FDA based on overall response rate and duration of response and continuation of support for these indications may be contingent upon the verification and description of continued clinical benefit in confirmatory trials.

FDA Label

Vitrakvi as monotherapy is indicated for the treatment of adult and paediatric patients with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion,

- who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and

- who have no satisfactory treatment options.

Treatment of malignant neoplasms of the central nervous system

Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms)

5 Pharmacology and Biochemistry

5.1 Pharmacology

At doses that are nine-fold greater than the recommended adult dose, larotrectinib does not elicit any QTc interval prolongation that is clinically relevant.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

LAROTRECTINIB

5.2.2 FDA UNII

PF9462I9HX

5.2.3 Pharmacological Classes

Tropomyosin Receptor Kinases Inhibitors [MoA]; Kinase Inhibitor [EPC]

5.3 ATC Code

L01XE53

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EX - Other protein kinase inhibitors

L01EX12 - Larotrectinib

5.4 Absorption, Distribution and Excretion

Absorption

The mean absolute bioavailability of larotrectinib capsules has been recorded as 34%, from a range spanning 32% to 37%. In adult patients who received larotrectinib capsules 100 mg twice daily, peak plasma levels Cmax were achieved at about one hour after dosing and steady-state was reached within the time span of three days. The mean steady-state of these administered larotrectinib capsules was Cmax 788 ng/mL and the AUC(0-24hr) was 4351 ng*h/mL. Concurrently, in healthy subjects, the AUC of the administered larotrectinib oral solution formulation was similar to that of the capsules and the particular Cmax was 36% greater with the oral solution. The AUC of larotrectinib was similar but the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of larotrectinib to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state.

Route of 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.

Volume of Distribution

The mean volume of distribution Vss of larotrectinib has been documented as being 48L following intravenous administration in healthy subjects.

Clearance

The mean clearance CL/F of larotrectinib has been documented as 98 L/h.

5.5 Metabolism/Metabolites

Larotrectinib is metabolized predominantly by the CYP3A4 isoenzymes. Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma.

5.6 Biological Half-Life

The half-life of larotrectinib has been determined to be 2.9 hours.

5.7 Mechanism of Action

Tropomysoin Receptor Kinases (TRK) like TRKA, TRKB, and TRKC elicit activities that regulate the natural growth, differentiation, and survival of neurons when they interact with endogenous neutrotrophin ligands. TRKA, TRKB, and TRKC are themselves encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. It has been discovered that chromosomal rearrangements involving in-frame fusions of these genes with various partners, translocations in the TRK kinase domains, mutations in the TRK ligand-binding site, amplifications of NTRK, or the expression of TRK splice variants can result in constitutively-activated chimeric TRK fusion proteins that can act as oncogenic drivers that promote cell proliferation and survival in tumor cell lines. Subsequently, larotrectinib functions as an inhibitor of TRKs including TRKA, B, and C. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

API SUPPLIERS