SEMAGLUTIDE

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/29363040 | https://www.drugbank.ca/drugs/DB13928

Semaglutide (trade name Ozempic) is a pharmaceutical drug in development by a Danish company Novo Nordisk for the treatment of type 2 diabetes. Semaglutide is a once-daily glucagon-like peptide-1 analog that differs to others by the presence of an acyl group with a steric diacid at Lys26 and a large synthetic spacer and modified by the presence of a α-aminobutyric acid in position 8 which gives stability against the dipeptidylpeptidase-4. Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors. The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is stabilized against degradation by the DPP-4 enzyme. Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Glucagon-like peptide 1 receptor 4 Target ID: CHEMBL1784 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/26308095	Agonist 2678		6.2 pM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: http://www.pharmacytimes.com/product-news/fda-approves-onceweekly-semaglutide-for-type-2-diabetes	Primary		Approved 8429	OZEMPIC Approved Use OZEMPIC is a glucagon-like peptide 1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Launch Date 2017

C_max

Value	Dose	Co-administered	Analyte	Population
9.5 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.7 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
3026 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3080 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
150 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
151 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29205786	0.5 mg single, subcutaneous dose: 0.5 mg route of administration: Subcutaneous experiment type: SINGLE co-administered:		SEMAGLUTIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213182s000,213051s001lbl.pdf	unknown, unknown		SEMAGLUTIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
20 ug/kg 1 times / day single, subcutaneous Highest studied dose Dose: 20 ug/kg, 1 times / day Route: subcutaneous Route: single Dose: 20 ug/kg, 1 times / day Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf	healthy, adult n = 6 Health Status: healthy Age Group: adult Sex: M Population Size: 6 Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf	Other AEs: Nausea, Vomiting... Other AEs: Nausea Vomiting Dyspepsia Headache Decreased appetite Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf
15 ug/kg 1 times / day single, subcutaneous MTD Dose: 15 ug/kg, 1 times / day Route: subcutaneous Route: single Dose: 15 ug/kg, 1 times / day Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf	healthy, adult n = 6 Health Status: healthy Age Group: adult Sex: M Population Size: 6 Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf	Other AEs: Nausea, Vomiting... Other AEs: Nausea Vomiting Dyspepsia Headache Decreased appetite Sources: https://distribute.m-anage.com/check.pic?path=events%5C176%5Cabstract%5C25575%5C343995_826.pdf
8 mg 1 times / day multiple, oral (mean) Recommended Dose: 8 mg, 1 times / day Route: oral Route: multiple Dose: 8 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213051Orig1s000MedR.pdf Page: 213051Orig1s000MedR.pdf -p.153, p.175	unhealthy, adult n = 4379 Health Status: unhealthy Condition: Type 2 diabetes Age Group: adult Sex: M+F Population Size: 4379 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213051Orig1s000MedR.pdf Page: 213051Orig1s000MedR.pdf -p.153, p.175	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (2.9%) Vomiting (1.7%) Diarrhea (0.9%) Abdominal pain (0.6%) Abdominal pain upper (0.5%) Abdominal discomfort (0.4%) Dyspepsia (0.3%) Constipation (0.3%) Abdominal distension (0.3%) Gastritis (0.2%) GERD (0.2%) Pancreatitis acute (0.2%) Decreased appetite (0.7%) Weight decreased (0.3%) Lipase increased (0.2%) Asthenia (0.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/213051Orig1s000MedR.pdf Page: 213051Orig1s000MedR.pdf -p.153, p.175
20 mg 1 times / day single, oral Highest studied dose Dose: 20 mg, 1 times / day Route: oral Route: single Dose: 20 mg, 1 times / day Co-administed with:: sodium N-(8-[2-hydroxybenzoyl]amino) caprylate(600 mg; single) Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	healthy, mean age 34.8 years n = 10 Health Status: healthy Age Group: mean age 34.8 years Sex: M Population Size: 10 Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/
1.5 mg 1 times / week multiple, subcutaneous Highest studied dose Dose: 1.5 mg, 1 times / week Route: subcutaneous Route: multiple Dose: 1.5 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/29799100/	healthy, mean age 37.7 years n = 83 Health Status: healthy Age Group: mean age 37.7 years Sex: M+F Population Size: 83 Sources: https://pubmed.ncbi.nlm.nih.gov/29799100/	Sources: https://pubmed.ncbi.nlm.nih.gov/29799100/
40 mg 1 times / day multiple, oral Highest studied dose Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Co-administed with:: sodium N-(8-[2-hydroxybenzoyl]amino) caprylate(300 mg; 10 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	healthy, mean age 40.8 years n = 32 Health Status: healthy Age Group: mean age 40.8 years Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	Disc. AE: Lipase increased, Decreased appetite... Other AEs: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Lipase increased (12.5%) Decreased appetite (6.25%) Nausea (6.25%) Vomiting (3.1%) Other AEs: Nausea (46.9%) Vomiting (40.6%) Eructation (43.8%) Abdominal pain (28.1%) Diarrhoea (12.5%) Abdominal distension (21.9%) Dyspepsia (31.3%) Abdominal discomfort (15.6%) Flatulence (12.5%) Abdominal pain upper (9.4%) Infrequent bowel movements (9.4%) Toothache (12.5%) Decreased appetite (78.1%) Nasopharyngitis (31.3%) Headache (37.5%) Fatigue (25%) Asthenia (9.4%) Lipase increased (21.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/
40 mg 1 times / day multiple, oral Highest studied dose Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Co-administed with:: sodium N-(8-[2-hydroxybenzoyl]amino) caprylate(300 mg; 10 weeks) Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	unhealthy, mean age 55.3 years n = 11 Health Status: unhealthy Condition: Type 2 diabetes Age Group: mean age 55.3 years Sex: M Population Size: 11 Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/	Disc. AE: Lipase increased, Vomiting... Other AEs: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Lipase increased (9.1%) Vomiting (9.1%) Aortic aneurysm (9.1%) Other AEs: Nausea (54.5%) Vomiting (45.5%) Eructation (27.3%) Diarrhoea (18.2%) Abdominal distension (9.1%) Dyspepsia (36.4%) Abdominal discomfort (27.3%) Flatulence (9.1%) Abdominal pain upper (9.1%) Decreased appetite (90.9%) Nasopharyngitis (18.2%) Headache (36.4%) Fatigue (18.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/30565096/
1.6 mg 1 times / week multiple, subcutaneous Highest studied dose Dose: 1.6 mg, 1 times / week Route: subcutaneous Route: multiple Dose: 1.6 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/26358288/	unhealthy, mean age 56.4 years n = 47 Health Status: unhealthy Condition: Type 2 diabetes Age Group: mean age 56.4 years Sex: M+F Population Size: 47 Sources: https://pubmed.ncbi.nlm.nih.gov/26358288/	Disc. AE: Gastrointestinal disorder (NOS)... Other AEs: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Gastrointestinal disorder (NOS) Other AEs: Nausea (57.4%) Vomiting (27.7%) Diarrhea (23.4%) Dyspepsia (12.8%) Constipation (6.4%) Nasopharyngitis (6.4%) Gastroenteritis (4.3%) Urinary tract infection (4.3%) Fatigue (12.8%) Asthenia (10.6%) Anorexia (31.9%) Decreased appetite (17%) Musculoskeletal and connective tissue disorders (8.5%) Hypertension (2.1%) Injury, poisoning and procedural complications (8.5%) Skin and subcutaneous tissue disorders (2.1%) Respiratory, thoracic and mediastinal disorders (2.1%) Cardiac disorders (2.1%) Psychiatric disorders (2.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/26358288/
1 mg 1 times / week multiple, subcutaneous Recommended Dose: 1 mg, 1 times / week Route: subcutaneous Route: multiple Dose: 1 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/31539622/	unhealthy, mean age 59.5 years n = 289 Health Status: unhealthy Condition: Type 2 diabetes Age Group: mean age 59.5 years Sex: M+F Population Size: 289 Sources: https://pubmed.ncbi.nlm.nih.gov/31539622/	Disc. AE: Nausea, Diarrhea... AEs leading to discontinuation/dose reduction: Nausea Diarrhea Vomiting Constipation Abdominal pain Sources: https://pubmed.ncbi.nlm.nih.gov/31539622/
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf	unknown Health Status: unknown Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf	Other AEs: Thyroid tumor... Other AEs: Thyroid tumor Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 CYP3A4/5 278 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT2 647 P-gp 1461 BCRP 699		CYP1A2 701 CYP2B6 547 CYP3A4/5 124

Drug as perpetrator

Target	Modality	Activity
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	no
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
CYP3A4/5 335	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	yes [IC50 2.95 uM]
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=72 Page: 72.0	yes [IC50 3.5 uM]
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >40 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 >5 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000PharmR.pdf#page=38 Page: 38.0

PubMed

Title	Date	PubMed
Semaglutide-the "new kid on the block" in the field of glucagon-like peptide-1 receptor agonists?	2017 Dec	29285508
Semaglutide: First Global Approval.	2018 Feb	29363040

Patents

Sample Use Guides

In Vivo Use Guide

Start at 0.25 mg once weekly. After 4 weeks, increase the dose to 0.5 mg once weekly. If after at least 4 weeks additional glycemic control is needed, increase to 1 mg once weekly (2.1).  Administer once weekly at any time of day, with or without meals (2.1).  If a dose is missed administer within 5 days of missed dose (2.1).  Inject subcutaneously in the abdomen, thigh, or upper arm (2.2).

Route of Administration: Other

In Vitro Use Guide

Semaglutide displaced [125I]-GLP1 from human GLP1 receptor expressed in BHK cells after 2 hrs in absence of human serum albumin with the IC50 value of 0.38 nM.

Name

Type

Language

SEMAGLUTIDE

Official Name

English

NN-9535

Code

English

semaglutide [INN]

Common Name

English

SEMAGLUTIDE [ORANGE BOOK]

Common Name

English

NN1535 LAISEMA COMPONENT SEMAGLUTIDE

Common Name

English

NN9535

Code

English

NNC-0113-0217

Code

English

SEMAGLUTIDE [MI]

Common Name

English

SEMAGLUTIDE [JAN]

Common Name

English

NN1535 ICOSEMA COMPONENT SEMAGLUTIDE

Common Name

English

OZEMPIC

Brand Name

English

CagriSema component semaglutide

Common Name

English

WEGOVY

Brand Name

English

Semaglutide [WHO-DD]

Common Name

English

NNC 0113-0217

Code

English

SEMAGLUTIDE [USAN]

Common Name

English

RYBELSUS

Brand Name

English

SEMAGLUTIDE COMPONENT OF NN1535 ICOSEMA

Common Name

English

Classification Tree Code System Code

WHO-ATC

A10BJ06