Identification

Summary

Tirzepatide is a dual GIP and GLP-1 receptor agonist used for the treatment of type II diabetes in adults as an adjunct to diet and exercise.

Brand Names
Mounjaro
Generic Name
Tirzepatide
DrugBank Accession Number
DB15171
Background

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Dual GIP/GLP-1 agonists gained increasing attention as new therapeutic agents for glycemic and weight control as they demonstrated better glucose control and weight loss compared to selective GLP-1 receptor agonists in preclinical and clinical trials.1

Tirzepatide is made up of a 39 amino acid linear synthetic peptide conjugated to a C20 fatty diacid moiety.1 Its protein sequence was based on the sequence of endogenous GIP and its pharmacological action on GLP-1 receptors is comparable to endogenous GIP; however, the long half-life of tirzepatide allows for a once-weekly dosing.2 Tirzepatide was approved by the FDA on May 13, 2022 for the treatment of adults with type 2 diabetes, making it the first and only GIP and GLP-1 receptor agonist for this indication.5

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Peptides
Protein Chemical Formula
C225H348N48O68
Protein Average Weight
4810.52 Da
Sequences
>Tirzepatide protein sequence
YXEGTFTSDYSIXLDKIAQKAFVQWLIAGGPSSGAPPPS
References:
  1. KEGG DRUG: Tirzepatide [Link]
Download FASTA Format
Synonyms
  • Tirzepatide
External IDs
  • LY3298176

Pharmacology

Indication

Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This drug has not been studied in patients with a history of pancreatitis. Tirzepatide is not indicated for use in patients with type 1 diabetes mellitus.4

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Tirzepatide is a synthetic peptide with glucose-lowering effects. It works to stimulate first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner.1,4 Tirzepatide was also shown to delay gastric emptying, lower fasting and postprandial glucose concentration, decrease food intake,4 and reduce body weight in patients with type 2 diabetes.2 Tirzepatide can increase insulin sensitivity.4

As the peptide is conjugated to a C20 fatty diacid moiety through a hydrophilic linker at the lysine residue at position 20, the drug is highly bound to albumin in the plasma, which prolongs its half-life.2

Mechanism of action

Glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) are expressed throughout the body, including pancreatic beta-cells and the gastrointestinal tract. They have been implicated in the pathophysiology of type II diabetes mellitus as GLP-1R signalling is involved in glucose control by enhancing glucose-stimulated insulin secretion, delaying gastric transit, decreasing plasma glucagon levels, and reducing body weight by activating anorexigenic pathways in the brain.1 Both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are peptide hormones involved in glucose homeostasis: they promote glucose-stimulated insulin secretion from the pancreatic beta-cells.2 However, GIP is the main incretin hormone that exerts insulinotropic effects in response to food intake.1,2

The exact mechanism of action of tirzepatide has not been fully elucidated; however, dual agonism at GIP and GLP-1R may contribute to the glycemic and weight control effects of the drug.2 Studies demonstrated that co-administration of GIP and a GLP-1R agonist more significantly increased insulin response and suppressed glucagon secretion compared to separate administration of either hormone alone.3 Tirzepatide binds to GIP and GLP-1R with high affinity.1,2 In vitro, tirzepatide has a comparable GIP receptor binding affinity to native GIP and five times lower GLP-1R affinity than that of native GLP-1.3 Tirzepatide potently activates the GLP-1R signalling pathway to stimulate glucose-dependent insulin secretion through activity at the GIP receptor (GIPR) or the GLP-1R.1 However, the role of GIPR agonism in the drug's mechanism of action requires further investigation, as the evidence of GIPR agonism on glycemic and weight control in preclinical and clinical studies are conflicting.2

TargetActionsOrganism
AGlucagon-like peptide 1 receptor
agonist
Humans
AGastric inhibitory polypeptide
agonist
Humans
Absorption

Over the dose range of 1-5 mg, the Cmax of tirzepatide ranged from 108 to 397 ng/mL.1 The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Following subcutaneous administration, the Tmax ranged from eight to 72 hours. The steady-state plasma concentrations were achieved following four weeks of once-weekly subcutaneous administration.4

As tirzepatide delays gastric emptying, it has the potential to affect the absorption of concomitantly administered oral medications. The US prescribing information recommends the use of caution when co-administering tirzepatide with other oral medications.4

Volume of distribution

Following subcutaneous administration, the mean steady-state volume of distribution was 9.5 L.1 The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes mellitus was approximately 10.3 L.4

Protein binding

Tirzepatide is 99% bound to plasma albumin.1,2,4

Metabolism

Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis.4

Route of elimination

Tirzepatide is primarily excreted via urine and feces, mostly in the form of metabolites. Unchanged parent drug was not detectable in urine and feces.4

Half-life

The half-life is approximately five days.2,4

Clearance

The apparent population mean clearance of tirzepatide is 0.061 L/h.4 The mean steady-state apparent clearance of tirzepatide was 0.056 L/h.1

Adverse Effects
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Toxicity

There is limited information regarding the LD50 and overdose of tirzepatide. In case of an overdosage, appropriate supportive treatment should be initiated with a sufficient amount of time for observation and treatment, as tirzepatide has a long half-life.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Tirzepatide.
AcebutololThe therapeutic efficacy of Tirzepatide can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Tirzepatide can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Tirzepatide.
Acetyl sulfisoxazoleThe therapeutic efficacy of Tirzepatide can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of hypoglycemia can be increased when Acetylsalicylic acid is combined with Tirzepatide.
AlbiglutideThe risk or severity of hypoglycemia can be increased when Albiglutide is combined with Tirzepatide.
AlclometasoneThe risk or severity of hyperglycemia can be increased when Alclometasone is combined with Tirzepatide.
AlogliptinThe risk or severity of hypoglycemia can be increased when Alogliptin is combined with Tirzepatide.
AmcinonideThe risk or severity of hyperglycemia can be increased when Amcinonide is combined with Tirzepatide.
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Food Interactions
  • Take with or without food. Food has no clinically significant effects on drug exposure.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MounjaroInjection, solution2.5 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag
MounjaroInjection, solution15 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag
MounjaroInjection, solution7.5 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag
MounjaroInjection, solution12.5 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag
MounjaroInjection, solution5 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag
MounjaroInjection, solution10 mg/0.5mLSubcutaneousEli Lilly and Company2022-05-13Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
OYN3CCI6QE
CAS number
2023788-19-2

References

General References
  1. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3. [Article]
  2. Frias JP: Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020 Nov;15(6):379-394. doi: 10.1080/17446651.2020.1830759. Epub 2020 Oct 8. [Article]
  3. Min T, Bain SC: The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther. 2021 Jan;12(1):143-157. doi: 10.1007/s13300-020-00981-0. Epub 2020 Dec 15. [Article]
  4. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use [Link]
  5. Eli Lilly and Company Investors News Release: FDA approves Lilly's Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes [Link]
RxNav
2601723
Wikipedia
Tirzepatide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentBMI >27 kg/m2 / Metabolic and Nutritional Disorders / Obesity1
3Active Not RecruitingTreatmentBMI >27 kg/m2 / Obesity3
3Active Not RecruitingTreatmentBMI >27 kg/m2 / Obesity / Type 2 Diabetes Mellitus1
3Active Not RecruitingTreatmentObesity1
3Active Not RecruitingTreatmentType 2 Diabetes Mellitus1
3CompletedTreatmentType 2 Diabetes Mellitus8
3Not Yet RecruitingTreatmentObesity / Sleep Apnea1
3RecruitingTreatmentDiabetes Mellitus / Endocrine System Diseases / Metabolic Diseases / Metabolism Disorder, Glucose / Type 2 Diabetes Mellitus1
3RecruitingTreatmentHeart Failure With Preserved Ejection Fraction (HFpEF) / Obesity1
3RecruitingTreatmentType 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous10 mg/0.5mL
Injection, solutionSubcutaneous12.5 mg/0.5mL
Injection, solutionSubcutaneous15 mg/0.5mL
Injection, solutionSubcutaneous2.5 mg/0.5mL
Injection, solutionSubcutaneous5 mg/0.5mL
Injection, solutionSubcutaneous7.5 mg/0.5mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<1 mg/mLhttps://www.selleckchem.com/msds/MSDS_P1206.pdf

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
GLP1R
Uniprot ID
P43220
Uniprot Name
Glucagon-like peptide 1 receptor
Molecular Weight
53025.22 Da
References
  1. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3. [Article]
  2. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.
Specific Function
Gastric inhibitory polypeptide receptor binding
Gene Name
GIP
Uniprot ID
P09681
Uniprot Name
Gastric inhibitory polypeptide
Molecular Weight
17107.37 Da
References
  1. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3. [Article]
  2. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D'Alessio DA, Haupt A: LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub 2018 Oct 3. [Article]
  2. Frias JP: Tirzepatide: a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab. 2020 Nov;15(6):379-394. doi: 10.1080/17446651.2020.1830759. Epub 2020 Oct 8. [Article]
  3. FDA Approved Drug Products: MOUNJARO (tirzepatide) Injection, for subcutaneous use [Link]

Drug created at May 20, 2019 14:55 / Updated at May 31, 2022 09:32