Identification
- Summary
Trofinetide is a drug used to treat Rett syndrome in children and adults.
- Brand Names
- Daybue
- Generic Name
- Trofinetide
- DrugBank Accession Number
- DB06045
- Background
Trofinetide is a novel synthetic analog of glypromate, also known as glycine–proline–glutamate (GPE), a naturally occurring protein in the brain and the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1).1 Trofinetide was approved by the FDA on March 10, 2023, for the treatment of Rett syndrome,5,6 which is an X-linked neurodevelopmental disorder characterized by a range of cognitive, motor, and autonomic symptoms.1 Trofinetide is believed to work by reducing inflammation and apoptosis of neurons.2
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Trofinetide (DB06045)
- Weight
- Average: 315.326
Monoisotopic: 315.143035408 - Chemical Formula
- C13H21N3O6
- Synonyms
- glycyl-L-2-methylprolyl-L-glutamic acid
- Trofinetide
- External IDs
- NNZ 2566
- NNZ-2566
Pharmacology
- Indication
Trofinetide is indicated for the treatment of Rett syndrome in adults and pediatric patients two years of age and older.4
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- Contraindications & Blackbox Warnings
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Trofinetide works to reduce and alleviate the symptoms of Rett syndrome.1 It is an analog of glypromate or glycine–proline–glutamate (GPE), a naturally occurring protein in the brain and the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1). GPE exhibits neuroprotective properties: it protects neurons from glutamate-mediated excitotoxicity and oxidative stress at nanomolar concentrations. With a longer half-life than GPE, trofinetide is believed to exhibit similar neuroprotective properties.2
- Mechanism of action
Most cases of Rett syndrome are associated with loss-of-function mutations in a gene encoding methyl CpG binding protein 2 (MECP2), a DNA binding protein with a role in epigenetic regulation of gene expression.1 These mutations are believed to lead to synaptic immaturation in the cortex, aberrant metabolism of brain cholesterol resulting in abnormal neuronal development, and abnormal neuronal signaling.3 Rett syndrome more commonly occurs in girls than boys.1
The exact mechanism of action of trofinetide in Rett syndrome has not been fully elucidated.4 In mice studies, GPE improved motor and cardiorespiratory function, increased brain weight, and prolonged the lifespan in MECP2-deficient mice. As a GPE analog, trofinetide similarly attenuated apoptosis and reduced infarct size in a dose-dependent manner in a rat model of hypoxic insult.1,2 Trofinetide exerts a multi-faceted action to reduce inflammation, excitotoxicity-induced tissue damage, and apoptosis, thereby protecting the neurons and their surrounding infrastructure.2
- Absorption
Systemic exposure to trofinetide was dose-proportional across the studied dose range. The Tmax is about two to three hours after administration. Based on the mass balance study, at least 84% of the administered oral dose of 12,000 mg trofinetide was absorbed.4
A high-fat meal had negligible effects on drug exposure and reduced the Cmax by approximately 20%.4
- Volume of distribution
Following oral administration, the apparent volume of distribution of trofinetide in healthy adult subjects was approximately 80 L. Minimal to no accumulation was observed following multiple-dose administration.4
- Protein binding
Protein binding to human plasma is less than 6%.4
- Metabolism
Trofinetide is not significantly metabolized by CYP450 enzymes. Hepatic metabolism is not a significant route of trofinetide elimination.4
- Route of elimination
Trofinetide is primarily excreted in urine, with minor excretion in feces. Approximately 80% of the dose recovered in urine was in the unchanged parent drug form.4
- Half-life
The effective elimination half-life of orally administered trofinetide in healthy subjects is about 1.5 hours.4
- Clearance
No information is available.
- Adverse Effects
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There is no information available regarding acute toxicity (LD50) and overdose of trofinetide.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The metabolism of Abemaciclib can be decreased when combined with Trofinetide. Acalabrutinib The metabolism of Acalabrutinib can be decreased when combined with Trofinetide. Acenocoumarol The metabolism of Acenocoumarol can be decreased when combined with Trofinetide. Albendazole The metabolism of Albendazole can be decreased when combined with Trofinetide. Alectinib The metabolism of Alectinib can be decreased when combined with Trofinetide. Alfuzosin The metabolism of Alfuzosin can be decreased when combined with Trofinetide. Alpelisib The metabolism of Alpelisib can be decreased when combined with Trofinetide. Alprazolam The metabolism of Alprazolam can be decreased when combined with Trofinetide. Ambrisentan The serum concentration of Ambrisentan can be increased when it is combined with Trofinetide. Aminophylline The metabolism of Aminophylline can be decreased when combined with Trofinetide. 
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- Take with or without food. Food decreases Cmax of trofinetide but has negligible effects on total drug exposure.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Daybue Solution 200 mg/1mL Oral Acadia Pharmaceuticals Inc. 2022-12-31 Not applicable US 
Categories
- Drug Categories
- Amino Acids
- Amino Acids, Acidic
- Amino Acids, Dicarboxylic
- Amino Acids, Peptides, and Proteins
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (weak)
- Cytochrome P-450 Enzyme Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- Peptides
- UGT1A9 Inhibitors
- UGT2B15 Inhibitors
- UGT2B7 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Oligopeptides
- Alternative Parents
- Glutamic acid and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Pyrrolidinecarboxamides / N-acylpyrrolidines / Heterocyclic fatty acids / Dicarboxylic acids and derivatives / Tertiary carboxylic acid amides / Secondary carboxylic acid amides / Amino acids show 6 more
- Substituents
- Aliphatic heteromonocyclic compound / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Amine / Amino acid / Amino acid or derivatives / Azacycle / Carbonyl group / Carboxamide group show 24 more
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- Z2ME8F52QL
- CAS number
- 853400-76-7
- InChI Key
- BUSXWGRAOZQTEY-SDBXPKJASA-N
- InChI
- InChI=1S/C13H21N3O6/c1-13(5-2-6-16(13)9(17)7-14)12(22)15-8(11(20)21)3-4-10(18)19/h8H,2-7,14H2,1H3,(H,15,22)(H,18,19)(H,20,21)/t8-,13-/m0/s1
- IUPAC Name
- (2S)-2-{[(2S)-1-(2-aminoacetyl)-2-methylpyrrolidin-2-yl]formamido}pentanedioic acid
- SMILES
- C[C@]1(CCCN1C(=O)CN)C(=O)N[C@@H](CCC(O)=O)C(O)=O
References
- General References
- Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM: Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemp Clin Trials. 2022 Mar;114:106704. doi: 10.1016/j.cct.2022.106704. Epub 2022 Feb 8. [Article]
- Bickerdike MJ, Thomas GB, Batchelor DC, Sirimanne ES, Leong W, Lin H, Sieg F, Wen J, Brimble MA, Harris PW, Gluckman PD: NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke. J Neurol Sci. 2009 Mar 15;278(1-2):85-90. doi: 10.1016/j.jns.2008.12.003. Epub 2009 Jan 20. [Article]
- Chahil G, Bollu PC: Rett Syndrome. . [Article]
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
- FDA News: FDA approves first treatment for Rett Syndrome [Link]
- Acadia Pharmaceuticals: Acadia Pharmaceuticals Announces U.S. FDA Approval of DAYBUE™ (trofinetide) for the Treatment of Rett Syndrome in Adult and Pediatric Patients Two Years of Age and Older [Link]
- External Links
- ChemSpider
- 9493869
- 2632852
- ChEMBL
- CHEMBL197084
- Wikipedia
- Trofinetide
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Rett Syndrome 3 2 Completed Supportive Care Brain Injury 1 2 Completed Treatment Brain Injury 1 2 Completed Treatment Fragile X Syndrome 1 2 Completed Treatment Rett Syndrome 2 2 Terminated Treatment Concussion, Brain 1 2, 3 Completed Treatment Rett Syndrome 1 1 Completed Treatment Traumatic Brain Injury (TBI) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Solution Oral 200 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11370755 No 2020-08-03 2040-08-03 US US9212204 No 2015-12-15 2032-01-27 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 655.4±55 https://www.chemsrc.com/en/cas/853400-76-7_1470449.html logP -2.22 https://www.chemsrc.com/en/cas/853400-76-7_1470449.html - Predicted Properties
Property Value Source Water Solubility 10.4 mg/mL ALOGPS logP -3 ALOGPS logP -4.5 Chemaxon logS -1.5 ALOGPS pKa (Strongest Acidic) 3.27 Chemaxon pKa (Strongest Basic) 7.83 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 4 Chemaxon Polar Surface Area 150.03 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 73.79 m3·mol-1 Chemaxon Polarizability 30.95 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this enzyme in vitro.
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this enzyme in vitro.
- General Function
- Retinoic acid binding
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1-9
- Molecular Weight
- 59940.495 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this enzyme in vitro.
- General Function
- Glucuronosyltransferase activity
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
- Gene Name
- UGT2B7
- Uniprot ID
- P16662
- Uniprot Name
- UDP-glucuronosyltransferase 2B7
- Molecular Weight
- 60694.12 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this enzyme in vitro.
- General Function
- Glucuronosyltransferase activity
- Specific Function
- UDPGTs are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isozyme displays activity toward several classes of xeno...
- Gene Name
- UGT2B15
- Uniprot ID
- P54855
- Uniprot Name
- UDP-glucuronosyltransferase 2B15
- Molecular Weight
- 61035.815 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this transporter in vitro.
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Trofinetide was found to be an inhibitor of this transporter in vitro.
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- FDA Approved Drug Products: DAYBUE (trofinetide) Oral Solution [Link]
Drug created at November 18, 2007 18:29 / Updated at April 07, 2023 13:12