Tirzepatide

Description

Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Tirzepatide is a GIP receptor and GLP-1 receptor agonist. It is a 39-amino-acid modified peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1. Tirzepatide enhances first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. Tirzepatide can also be used off-label for treating obesity. It is currently implemented as a second-line diabetes medication, similar to GLP-1 medications like semaglutide. It is a once-a-week subcutaneous injectable medication with incremental dose increases.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Gastric inhibitory polypeptide receptor	Agonist 2,678		0.135 nM [Ki]
Glucagon-like peptide 1 receptor 4	Agonist 2,678		4.23 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259	Primary		Approved 8,429	MOUNJARO

C_max

Value	Dose	Analyte	Population
664 ng/mL	5 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1340 ng/mL	10 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1990 ng/mL	15 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
26 ng/mL	0.25 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
57.7 ng/mL	0.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
108 ng/mL	1 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
231 ng/mL	2.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
397 ng/mL	5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
874 ng/mL	8 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
77.8 ng/mL	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
198 ng/mL	1.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
884 ng/mL	4.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1510 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
54.6 ng/mL	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
614 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1030 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1250 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1520 ng/mL	2.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
2270 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
838 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
663 ng/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1270 ng/mL	7.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
1900 ng/mL	10 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
83300 ng × h/mL	5 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
168000 ng × h/mL	10 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
250000 ng × h/mL	15 mg 1 times / week steady-state, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
5760 ng × h/mL	0.25 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
12000 ng × h/mL	0.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
22600 ng × h/mL	1 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
53200 ng × h/mL	2.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
90500 ng × h/mL	5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
169000 ng × h/mL	8 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
10600 ng × h/mL	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
24800 ng × h/mL	1.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
103000 ng × h/mL	4.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
198000 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
7200 ng × h/mL	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
81900 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
131000 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
164000 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
192000 ng × h/mL	2.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
285000 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
104000 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
68900 ng × h/mL	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
149000 ng × h/mL	7.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
5 day	5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
116 h	0.25 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
124 h	0.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
108 h	1 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
120 h	2.5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
123 h	5 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
111 h	8 mg single, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
152 h	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
113 h	1.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
132 h	4.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
126 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
120 h	0.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
114 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
115 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
104 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
135 h	2.5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
121 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens
127 h	5 mg 1 times / week multiple, subcutaneous	TIRZEPATIDE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.94%			TIRZEPATIDE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT	Disc. AE: Diarrhea, Nausea...

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AEs

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AE	Significance	Dose	Population
Blood calcitonin increased	0.3% Disc. AE	15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT
Colitis ischaemia	0.3% Disc. AE	15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT
Abdominal discomfort	0.6% Disc. AE	15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT
Dyspepsia	0.6% Disc. AE	15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT
Nausea	0.8% Disc. AE	15 mg 1 times / week multiple, subcutaneous Highest studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1,767 inducer 389	inducer 97 inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2B6 810 OAT3 642 CYP2C8 911 P-gp 1,461 CYP3A 214 BCRP 699 OATP1B1 788 OATP1B3 706 OCT1 512 OCT2 647 OAT1 599 CYP2C19 1,478 MATE1 306 MATE2K		CYP2B6 547 CYP2C19 293 CYP2C8 168 CYP3A5 76 CYP1A2 701

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no [IC50 >100 uM]
CYP2B6 1,001	inhibitor 3,277	no [IC50 >100 uM]
CYP2C19 1,553	inhibitor 3,277	no [IC50 >100 uM]
CYP2C8 965	inhibitor 3,277	no [IC50 >100 uM]
CYP2C9 1,819	inhibitor 3,277	no [IC50 >100 uM]

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

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Title	Date	PubMed
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.	2020 Sep 3	32730231
Tirzepatide: First Approval.	2022 Jul	35830001

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended starting dosage is 2.5 mg injected subcutaneously once weekly (2.1) After 4 weeks, increase to 5 mg injected subcutaneously once weekly (2.1) If additional glycemic control is needed, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose. The maximum dosage is 15 mg subcutaneously once weekly (2.1). Administer once weekly at any time of day, with or without meals. (2.2) Inject subcutaneously in the abdomen, thigh, or upper arm. (2.2) Rotate injection sites with each dose.

Route of Administration: Subcutaneous

In Vitro Use Guide

In signaling studies using cell lines with recombinantly expressed GIPR or GLP-1R, LY3298176 potently stimulates cAMP accumulation by either receptor (GIPR EC50 = 0.0224, SEM = 0.0053 nM; GLP-1R EC50 = 0.934, SEM = 0.068 nM)

Substance Class	Protein
Protein Sub Type
Sequence Type	COMPLETE
Record UNII	OYN3CCI6QE
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Tirzepatide

Official Name

English

LY3298176

Code

English

LY-3298176

Code

English

TIRZEPATIDE [USAN]

Common Name

English

L-Tyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-L-lysyl-L-isoleucyl-L-alanyl-L-glutaminyl-N6-[(22S)-22,42-dicarboxy-1,10,19,24-tet

Systematic Name

English

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Code System

Code

Type

Description

USAN

EF-81

PRIMARY

FDA UNII

OYN3CCI6QE

PRIMARY

DAILYMED

OYN3CCI6QE

PRIMARY

INN

10849

PRIMARY

WIKIPEDIA

Tirzepatide

PRIMARY

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Subunit 0

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Related Record

Type

Details


					EF38T7N5MI

GLUCAGON-LIKE PEPTIDE 1 RECEPTOR

TARGET->PARTIAL AGONIST

Comments:

On GLP-1R, TZP is a partial agonist 51% stimulation. shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment.

Qualification:

EC50

Amount:

0.617 NANOMOLAR [0.427 to 0.807] (average)


					D6H00MV7K8

GASTRIC INHIBITORY POLYPEPTIDE RECEPTOR

TARGET -> AGONIST

Comments:

GTPγS binding of Gαs in GIPR versus GIP(1-42) of 1.43 nM

Qualification:

EC50

Amount:

0.379 NANOMOLAR [0.309 to 0.449] (average)

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Related Record

Type

Details


					OYN3CCI6QE

Tirzepatide

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Referenced Substance	Defining	Parameters	References
MOL_WEIGHT:SEQUENCE(CALCULATED)	CHEMICAL	SEQUENCE 4813 DA (average)
Molecular Formula	CHEMICAL	ESTIMATED C225H347O66N49

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CNS Activity

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator