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Alpelisib

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ACTIVE PHARMA INGREDIENTS

6 API Suppliers, 1 KDMF, 6 Listed Suppliers

6 API Suppliers
1 KDMF
6 Listed Suppliers

DEVELOPMENTS

8 Drugs in Development

8 Drugs in Development

FINISHED DOSAGE FORMULATIONS

20 FDF Dossiers, 7 FDA Orange Book, 5 Europe, 4 Canada, 4 South Africa

20 FDF Dossiers
7 FDA Orange Book
5 Europe
4 Canada
4 South Africa

DIGITAL CONTENT

3 DATA COMPILATION #PharmaFlow, 28 NEWS #PharmaBuzz

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3 DATA COMPILATION #PharmaFlow
28 NEWS #PharmaBuzz

GLOBAL SALES INFORMATION

2 US Medicaid Prescriptions, 5 Finished Drug Prices, 5 Annual Reports

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2 US Medicaid Prescriptions
5 Finished Drug Prices
5 Annual Reports

MARKET PLACE

2 APIs

marketPlace
2 APIs

PATENTS & EXCLUSIVITIES

14 US Patents, 12 US Exclusivities

patents
14 US Patents
12 US Exclusivities

Synopsis

ACTIVE PHARMA INGREDIENTS

API Suppliers

USDMF

CEP/COS

JDMF

EU WC

KDMF

NDC API

VMF

Listed Suppliers

API REF. PRICE (USD/KG)

$ 0

MARKET PLACE

API

FDF

0INTERMEDIATES

FINISHED DOSAGE FORMULATIONS

FDF Dossiers

FDA Orange Book

Europe

Canada

Australia

South Africa

Listed Dossiers

8DRUGS IN DEVELOPMENT

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)

124,139,868

Annual Reports (USD Million)

1,643

Finished Drug Prices

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Chemistry

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Also known as: 1217486-61-7, Byl-719, Byl719, Piqray, Nvp-byl719, Vijoice

Molecular Formula

C₁₉H₂₂F₃N₅O₂S

Molecular Weight

441.5 g/mol

InChI Key

STUWGJZDJHPWGZ-LBPRGKRZSA-N

FDA UNII

08W5N2C97Q

Alpelisib is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. Alpelisib specifically inhibits PI3K in the PI3K/AKT kinase (or protein kinase B) signaling pathway, thereby inhibiting the activation of the PI3K signaling pathway. This may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.

1 2D Structure

Alpelisib

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S)-1-N-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide

2.1.2 InChI

InChI=1S/C19H22F3N5O2S/c1-10-14(11-6-7-24-13(9-11)18(2,3)19(20,21)22)30-16(25-10)26-17(29)27-8-4-5-12(27)15(23)28/h6-7,9,12H,4-5,8H2,1-3H3,(H2,23,28)(H,25,26,29)/t12-/m0/s1

2.1.3 InChI Key

STUWGJZDJHPWGZ-LBPRGKRZSA-N

2.1.4 Canonical SMILES

CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F

2.1.5 Isomeric SMILES

CC1=C(SC(=N1)NC(=O)N2CCC[C@H]2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F

2.2 Other Identifiers

2.2.1 UNII

08W5N2C97Q

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Byl719

2. Nvp-byl719

3. Piqray

2.3.2 Depositor-Supplied Synonyms

1. 1217486-61-7

2. Byl-719

3. Byl719

4. Piqray

5. Nvp-byl719

6. Vijoice

7. Alpelisib (byl719)

8. (s)-n1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

9. Byl 719

10. Chembl2396661

11. 08w5n2c97q

12. (2s)-n1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide

13. (2s)-1-n-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide

14. (s)-pyrrolidine-1,2-dicarboxylic Acid 2-amide 1-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-pyridin-4-yl)thiazol-2-yl)amide

15. 1,2-pyrrolidinedicarboxamide, N1-(4-methyl-5-(2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl)-2-thiazolyl)-, (2s)-

16. 1,2-pyrrolidinedicarboxamide, N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-, (2s)-

17. Alpelisib [inn]

18. (2s)-n~1~-{4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide

19. (s)-n1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide.

20. Unii-08w5n2c97q

21. 4jps

22. 1lt

23. Alpelisib [usan]

24. Piqray (tn)

25. Alpelisib [jan]

26. Alpelisib [mi]

27. Alpelisib [usan:inn]

28. Alpelisib [who-dd]

29. Alpelisib (jan/usan/inn)

30. Gtpl7955

31. Schembl1911869

32. Alpelisib [orange Book]

33. Chebi:93752

34. Dtxsid70153355

35. Ex-a405

36. Byl 719; Byl719

37. Bdbm50436459

38. Mfcd22417085

39. Nsc765974

40. Nsc800065

41. S2814

42. Zinc68198368

43. Akos022186315

44. Ccg-269139

45. Cs-0663

46. Db12015

47. Nsc-765974

48. Nsc-800065

49. Ncgc00346717-03

50. Ncgc00346717-06

51. (2s)-n1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidine

52. 1217486-47-9

53. As-16349

54. Hy-15244

55. Sw220128-1

56. Cas:1217486-61-7;byl-719

57. D11011

58. A855666

59. J-004627

60. Q27074391

61. (2s)-n1-(4-methyl-5-(1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)-1,3-thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

62. (2s)-n1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide;alpelisib

2.4 Create Date

2012-03-05

3 Chemical and Physical Properties

Molecular Formula	C₁₉H₂₂F₃N₅O₂S
Molecular Weight	441.5 g/mol
XLogP3	3.2
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	4
Exact Mass	441.14463062 g/mol
Monoisotopic Mass	441.14463062 g/mol
Topological Polar Surface Area	129 Å²
Heavy Atom Count	30
Formal Charge	0
Complexity	663
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
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

Alpelisib is indicated in combination with fulvestrant to treat postmenopausal women, and men, with advanced or metastatic breast cancer. This cancer must be hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and PIK3CA mutated. The cancer must be detected by an FDA-approved test following progression on or after an endocrine-based regimen.

FDA Label

Treatment of breast cancer

Piqray is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy (see section 5. 1).

Treatment of PIK3CA related overgrowth spectrum

Treatment of Fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours), Treatment of ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours), Treatment of peritoneal carcinoma (excluding blastomas and sarcomas)

5 Pharmacology and Biochemistry

5.1 Pharmacology

Alpelisib does not prolong the QTcF interval. Patients taking alpelisib experience a dose dependent benefit from treatment with a 51% advantage of a 200mg daily dose over a 100mg dose and a 22% advantage of 300mg once daily over 150mg twice daily. This suggests patients requiring a lower dose may benefit from twice daily dosing.

5.2 ATC Code

L01XE

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01E - Protein kinase inhibitors

L01EM - Phosphatidylinositol-3-kinase (pi3k) inhibitors

L01EM03 - Alpelisib

5.3 Absorption, Distribution and Excretion

Absorption

Alpelisib reached a peak concentration in plasma of 1320912ng/mL after 2 hours. Alpelisib has an AUC_last of 11,1003760h ng/mL and an AUC_INF of 11,1003770h ng/mL. A large, high fat meal increases the AUC by 73% and C_max by 84% while a small, low fat meal increases the AUC by 77% and C_max by 145%.

Route of Elimination

36% of an oral dose is eliminated as unchanged drug in the feces and 32% as the primary metabolite BZG791 in the feces. 2% of an oral dose is eliminated in the urine as unchanged drug and 7.1% as the primary metabolite BZG791. In total 81% of an oral dose is eliminated in the feces and 14% is eliminated in the urine.

Volume of Distribution

The apparent volume of distribution at steady state is 114L.

Clearance

The mean apparent oral clearance was 39.0L/h. The predicted clearance is 9.2L/hr under fed conditions.

5.4 Metabolism/Metabolites

Alpelisib is metabolized by hydrolysis reactions to form the primary metabolite. It is also metabolized by CYP3A4. The full metabolism of Alpelisib has yet to be determined but a series of reactions have been proposed. The main metabolic reaction is the substitution of an amine group on alpelisib for a hydroxyl group to form a metabolite known as M4 or BZG791. Alpelisib can also be glucuronidated to form the M1 and M12 metabolites.

5.5 Biological Half-Life

The mean half life of alprelisib is 8 to 9 hours.

5.6 Mechanism of Action

Phosphatidylinositol-3-kinase- (PI3K) is responsible for cell proliferation in response to growth factor-tyrosine kinase pathway activation. In some cancers PI3K's p110 catalytic subunit is mutated making it hyperactive. Alpelisib inhibits (PI3K), with the highest specificity for PI3K.

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