Details of the Drug

General Information of Drug (ID: DMEXMYK)

Drug Name

Alpelisib

Synonyms

alpelisib; 1217486-61-7; BYL-719; BYL719; UNII-08W5N2C97Q; BYL 719; Alpelisib (BYL719); (S)-N1-(4-Methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide; NVP-BYL719; (2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide; CHEMBL2396661; 08W5N2C97Q; AK146107; C19H22F3N5O2S; (S)-N1-(4-Methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide

Indication

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[1]
Solid tumour/cancer	2A00-2F9Z	Phase 2	[2], [3]

Drug Type

Small molecular drug

Structure

3D MOL

2D MOL

#Ro5 Violations (Lipinski): 0

Molecular Weight (mw)

441.5

Topological Polar Surface Area (xlogp)

3.2

Rotatable Bond Count (rotbonds)

4

Hydrogen Bond Donor Count (hbonddonor)

2

Hydrogen Bond Acceptor Count (hbondacc)

8

ADMET Property

Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 11,100 +/- 3760 mcgh/L [4]
Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1320 +/- 912 mcg/L [4]
Absorption Tmax: The time to maximum plasma concentration (Tmax) is 2 h [4]
Clearance: The apparent oral clearance of drug is 39.0 L/h [4]
Half-life: The concentration or amount of drug in body reduced by one-half in 8 - 9 hours [5]
Metabolism: The drug is metabolized via the hydrolysis reactions [4]
Vd: The volume of distribution (Vd) of drug is 114 L [6]

Chemical Identifiers

Formula: C19H22F3N5O2S
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
Canonical SMILES: CC1=C(SC(=N1)NC(=O)N2CCC[C@H]2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F
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
InChIKey: STUWGJZDJHPWGZ-LBPRGKRZSA-N

Cross-matching ID

PubChem CID: 56649450
ChEBI ID: CHEBI:93752
CAS Number: 1217486-61-7
DrugBank ID: DB12015
TTD ID: D0W7HE
INTEDE ID: DR0074
ACDINA ID: D00827

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
PI3-kinase alpha (PIK3CA)	TTEUNMR	PK3CA_HUMAN	Inhibitor	[1]

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Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)_{Main DME}	DE4LYSA	CP3A4_HUMAN	Substrate	[7]

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Molecular Interaction Atlas (MIA)

MIA Detail

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Molecular Expression Atlas of This Drug

ICD Disease Classification

02 Neoplasm

Disease Class

ICD-11: 2C82 Prostate cancer

The Studied Tissue

Breast tissue

The Studied Disease

Breast cancer [ICD-11:2C82]

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
PI3-kinase alpha (PIK3CA)	DTT	PIK3CA	1.59E-38	-0.65	-1.11
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	1.87E-03	-6.67E-02	-2.12E-01

Molecular Expression Atlas (MEA)

MEA Detail

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Drug-Drug Interaction (DDI) Information of This Drug

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

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Ivosidenib	DM8S6T7	Moderate	Increased metabolism of Alpelisib caused by Ivosidenib mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[27]
Ag-221	DMS0ZBI	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Ag-221.	BCR-ABL1-negative chronic myeloid leukaemia [2A41]	[28]
Pexidartinib	DMS2J0Z	Moderate	Increased metabolism of Alpelisib caused by Pexidartinib mediated induction of CYP450 enzyme.	Bone/articular cartilage neoplasm [2F7B]	[27]
Ripretinib	DM958QB	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Ripretinib.	Gastrointestinal stromal tumour [2B5B]	[28]
MK-1439	DM215WE	Moderate	Increased metabolism of Alpelisib caused by MK-1439 mediated induction of CYP450 enzyme.	Human immunodeficiency virus disease [1C60-1C62]	[27]
PF-06463922	DMKM7EW	Moderate	Increased metabolism of Alpelisib caused by PF-06463922 mediated induction of CYP450 enzyme.	Lung cancer [2C25]	[27]
Ubrogepant	DM749I3	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Ubrogepant.	Migraine [8A80]	[29]
Rimegepant	DMHOAUG	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Rimegepant.	Migraine [8A80]	[30]
Siponimod	DM2R86O	Moderate	Increased metabolism of Alpelisib caused by Siponimod mediated induction of CYP450 enzyme.	Multiple sclerosis [8A40]	[27]
Lefamulin	DME6G97	Moderate	Decreased metabolism of Alpelisib caused by Lefamulin mediated inhibition of CYP450 enzyme.	Pneumonia [CA40]	[31]
Telotristat ethyl	DMDIYFZ	Moderate	Increased metabolism of Alpelisib caused by Telotristat ethyl mediated induction of CYP450 enzyme.	Small intestine developmental anomaly [DA90]	[27]
Larotrectinib	DM26CQR	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Larotrectinib.	Solid tumour/cancer [2A00-2F9Z]	[28]
Lusutrombopag	DMH6IKO	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Lusutrombopag.	Thrombocytopenia [3B64]	[32]
Betrixaban	DM2C4RF	Moderate	Decreased clearance of Alpelisib due to the transporter inhibition by Betrixaban.	Venous thromboembolism [BD72]	[33]
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⏷ Show the Full List of 14 DDI Information of This Drug

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

DIG

DIG Name	DIG ID	PubChem CID	Functional Classification
Mannitol	E00103	6251	Diluent; Flavoring agent; Lyophilization aid; Plasticizing agent; Tonicity agent
Ferric oxide black	E00522	16211978	Colorant
Hypromellose	E00634	Not Available	Coating agent
Magnesium stearate	E00208	11177	lubricant
Polyethylene glycol 4000	E00654	Not Available	Coating agent; Diluent; Ointment base; Plasticizing agent; Solvent; Suppository base; lubricant
Talc	E00520	16211421	Anticaking agent; Diluent; Glidant; lubricant
Titanium dioxide	E00322	26042	Coating agent; Colorant; Opacifying agent
Haematite red	E00236	14833	Colorant
Cellulose microcrystalline	E00698	Not Available	Adsorbent; Suspending agent; Diluent
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⏷ Show the Full List of 9 Pharmaceutical Excipients of This Drug

Pharmaceutical Formulation

Formulation Name	Drug Dosage	Dosage Form	Route
Alpelisib 50mg tablet	50mg	Tablet	Oral
Alpelisib 150mg tablet	150mg	Tablet	Oral
Alpelisib 200mg tablet	200mg	Tablet	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	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7955).
3	ClinicalTrials.gov (NCT01923168) Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women. U.S. National Institutes of Health.
4	Teramura T, Watanabe T, Higuchi S, Hashimoto K: Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation. Xenobiotica. 1997 Feb;27(2):203-16. doi: 10.1080/004982597240695 .
5	Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
6	An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
7	Comparison of 19F NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans. Drug Metab Dispos. 2017 Aug;45(8):900-907.
8	Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
9	Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
10	Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
11	Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
12	Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
13	Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
14	Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
15	The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
16	Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
17	2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
18	Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
19	Company report (BioOncology)
20	Company report (Lilly)
21	The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
22	National Cancer Institute Drug Dictionary (drug id 714372).
23	Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
24	In vitro anticancer activity of PI3K alpha selective inhibitor BYL719 in head and neck cancer. Anticancer Res. 2015 Jan;35(1):175-82.
25	Adaptive resistance to PI3Kalpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells. Cell Death Dis. 2021 Jan 14;12(1):85.
26	ETP-46321, a dual p110alpha/ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis. Biochem Pharmacol. 2016 Apr 15;106:56-69.
27	Product Information. Piqray (alpelisib). Novartis Pharmaceuticals, East Hanover, NJ.
28	Cerner Multum, Inc. "Australian Product Information.".
29	Product Information. Ubrelvy (ubrogepant). Allergan Inc, Irvine, CA.
30	Product Information. Nurtec ODT (rimegepant). Biohaven Pharmaceuticals, New Haven, CT.
31	Product Information. Fycompa (perampanel). Eisai Inc, Teaneck, NJ.
32	EMA. European Medicines Agency. European Union "EMA - List of medicines under additional monitoring.".
33	Product Information. Bevyxxa (betrixaban). Portola Pharmaceuticals, South San Francisco, CA.