Identification
- Summary
Trifarotene is a topical retinoid indicated for the treatment of acne vulgaris.
- Brand Names
- Aklief
- Generic Name
- Trifarotene
- DrugBank Accession Number
- DB12808
- Background
Trifarotene is a topical retinoid cream used in the treatment of acne vulgaris that was first approved for use in the United States in October 2019.6 Retinoids are a class of medications structurally and functionally analogous to vitamin A, though later generation retinoids such as trifarotene and adapalene bear little structural resemblance to vitamin A and are analogous only in function.5 Trifarotene is considered the first of the "fourth-generation" retinoids due to its uniquely selective activity - this selectivity appears to confer improved efficacy and reduced side effects as compared to older, less selective retinoids.1
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Trifarotene (DB12808)
- Weight
- Average: 459.586
Monoisotopic: 459.240958547 - Chemical Formula
- C29H33NO4
- Synonyms
- Trifarotene
- External IDs
- CD-5789
- CD5789
Pharmacology
- Indication
Trifarotene is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.6
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Acne vulgaris •••••••••••• ••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Trifarotene exerts its effects via agonism at retinoid receptors - these receptors function to alter DNA transcription, resulting in downstream modulation of the expression of various genes involved in acne pathogenesis.5 It may be associated with skin irritation and should not be applied to cuts, abrasions, or otherwise damaged skin. As trifarotene may result in photosensitivity, patients should be cautioned to avoid excess sun exposure and to use sunscreen and/or protective clothing if exposure is unavoidable.6
- Mechanism of action
Trifarotene is a potent and selective agonist of retinoic acid receptor-γ (RAR-γ). It has significantly less activity at RAR-β and RAR-α (16- and 65-fold lower than activity at RAR-γ, respectively), and has no activity at retinoid X receptors (RXRs).1 Agonism at retinoic acid receptors results in dimerization, and the resulting receptor-ligand dimer binds to specific DNA regulatory sequences (retinoic acid response elements, or RAREs) in the promotor regions of retinoid-responsible genes. Downstream alterations to gene expression induced by binding to these regions is the principle mechanism through which trifarotene exerts its comedolytic, anti-inflammatory, and depigmenting effects.6
Like other retinoids, trifarotene influences the expression of a number of genes involved in retinoid metabolism, epidermal differentiation/proliferation, and epidermal response to stress. In addition, trifarotene appears to modulate retinoid-mediated pathways involved in proteolysis, skin hydration, and cell adhesion - modulation of these additional pathways has not been observed with other retinoids and may therefore be unique to trifarotene.1
Target Actions Organism ARetinoic acid receptor gamma agonistHumans URetinoic acid receptor beta agonistHumans URetinoic acid receptor alpha agonistHumans - Absorption
Systemic absorption of trifarotene is minimal. In a pharmacokinetic study involving 19 subjects, systemic concentrations were only quantifiable in 7 - steady state Cmax values ranged from undetectable (<5 pg/mL) to 10 pg/mL and AUC0-24h ranged from 75 to 104 pg.h/mL.6
- Volume of distribution
Not Available
- Protein binding
Trifarotene is 99.9% protein bound in plasma.6
- Metabolism
Trifarotene is rapidly metabolized in human hepatocytes - its observed half-life in human keratinocytes is >24 hours, whereas half-life in human liver microsomes is approximately 5 minutes.1 Metabolism of trifarotene is catalyzed primarily by CYP2C9, CYP3A4, CYP2C8, and, to a lesser extent, CYP2B6.6
- Route of elimination
Trifarotene is eliminated primarily in the feces.6
- Half-life
The terminal half-life of trifarotene is typically between 2 to 9 hours.6
- Clearance
Not Available
- Adverse Effects
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Trifarotene does not appear to carry any risk of carcinogenesis when used at standard doses.6 Systemic exposures in mice following both topical and oral administration were up to 1642 times higher than those seen in humans at the maximal recommended human dose, and these systemic concentrations did not result in observed carcinogenicity. Data regarding overdosage of trifarotene is unavailable.
- 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.Not Available
- Food Interactions
- No interactions found.
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 Aklief Cream 50 ug/1g Topical Galderma Laboratories, L.P. 2019-10-04 Not applicable US 
Aklief Cream 50 mcg / g Topical Galderma 2019-11-28 Not applicable Canada 
Categories
- ATC Codes
- D10AD06 — Trifarotene
- Drug Categories
- Alkenes
- Anti-Acne Preparations
- Anti-Acne Preparations for Topical Use
- Cytochrome P-450 CYP2B6 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Dermatologicals
- Misc. Skin and Mucous Membrane Agents
- Polyenes
- Retinoids
- Retinoids for Topical Use in Acne
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as m-terphenyls. These are terphenyls with a structure containing the 1,3-diphenylbenzene skeleton.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Terphenyls
- Direct Parent
- M-terphenyls
- Alternative Parents
- Biphenyls and derivatives / Phenylpyrrolidines / Benzoic acids / Phenylpropanes / Aniline and substituted anilines / Benzoyl derivatives / Dialkylarylamines / Phenol ethers / Phenoxy compounds / Alkyl aryl ethers show 7 more
- Substituents
- 1-phenylpyrrolidine / Alcohol / Alkyl aryl ether / Amine / Amino acid / Amino acid or derivatives / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Azacycle / Benzoic acid show 23 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 0J8RN2W0HK
- CAS number
- 895542-09-3
- InChI Key
- MFBCDACCJCDGBA-UHFFFAOYSA-N
- InChI
- InChI=1S/C29H33NO4/c1-29(2,3)25-19-23(10-12-26(25)30-14-4-5-15-30)24-18-22(11-13-27(24)34-17-16-31)20-6-8-21(9-7-20)28(32)33/h6-13,18-19,31H,4-5,14-17H2,1-3H3,(H,32,33)
- IUPAC Name
- 3'-[3-tert-butyl-4-(pyrrolidin-1-yl)phenyl]-4'-(2-hydroxyethoxy)-[1,1'-biphenyl]-4-carboxylic acid
- SMILES
- CC(C)(C)C1=CC(=CC=C1N1CCCC1)C1=CC(=CC=C1OCCO)C1=CC=C(C=C1)C(O)=O
References
- Synthesis Reference
Thoreau, E. et. al. Structure-based design of Trifarotene (CD5789), a potent and selective RARγ agonist for the treatment of acne. Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 10. 2018.
- General References
- Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, Dreno B, Gamboa B, Jomard A, Luzy AP, Mauvais P, Mounier C, Pascau J, Pelisson I, Portal T, Rivier M, Rossio P, Thoreau E, Vial E, Voegel JJ: Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4. [Article]
- Balak DMW: Topical trifarotene: a new retinoid. Br J Dermatol. 2018 Aug;179(2):231-232. doi: 10.1111/bjd.16733. [Article]
- Blume-Peytavi U, Fowler J, Kemeny L, Draelos Z, Cook-Bolden F, Dirschka T, Eichenfield L, Graeber M, Ahmad F, Alio Saenz A, Rich P, Tanghetti E: Long-term safety and efficacy of trifarotene 50 mug/g cream, a first-in-class RAR-gamma selective topical retinoid, in patients with moderate facial and truncal acne. J Eur Acad Dermatol Venereol. 2019 Jul 15. doi: 10.1111/jdv.15794. [Article]
- Tan J, Thiboutot D, Popp G, Gooderham M, Lynde C, Del Rosso J, Weiss J, Blume-Peytavi U, Weglovska J, Johnson S, Parish L, Witkowska D, Sanchez Colon N, Alio Saenz A, Ahmad F, Graeber M, Stein Gold L: Randomized phase 3 evaluation of trifarotene 50 mug/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019 Jun;80(6):1691-1699. doi: 10.1016/j.jaad.2019.02.044. Epub 2019 Feb 22. [Article]
- Chien A: Retinoids in Acne Management: Review of Current Understanding, Future Considerations, and Focus on Topical Treatments J Drugs Dermatol. 2018 Dec 1;17(12):s51-55. [Article]
- FDA Approved Drugs: Aklief® [Link]
- External Links
- PubChem Compound
- 11518241
- PubChem Substance
- 347828982
- ChemSpider
- 9693029
- 2205637
- ChEMBL
- CHEMBL3707313
- Wikipedia
- Trifarotene
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Acne Vulgaris 3 3 Completed Other Acne Vulgaris 1 3 Completed Treatment Acne Vulgaris 4 2 Completed Treatment Acne Vulgaris 1 2 Terminated Treatment Lamellar Ichthyosis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cream Cutaneous 0.005 g Cream Topical 50 ug/1g Cream Topical 50 mcg / g Cream Topical - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8470871 No 2013-06-25 2025-12-21 US US9084778 No 2015-07-21 2033-05-30 US US8227507 No 2012-07-24 2025-12-21 US US7807708 No 2010-10-05 2026-10-01 US US9498465 No 2016-11-22 2033-05-30 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 245C FDA Label pKa 5.69 (pKa1) FDA Label - Predicted Properties
Property Value Source Water Solubility 0.000945 mg/mL ALOGPS logP 6.12 ALOGPS logP 5.15 Chemaxon logS -5.7 ALOGPS pKa (Strongest Acidic) 3.97 Chemaxon pKa (Strongest Basic) 4.75 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 70 Å2 Chemaxon Rotatable Bond Count 8 Chemaxon Refractivity 136.98 m3·mol-1 Chemaxon Polarizability 53.11 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-01ox-1000900000-33bb49a6afed7268860f Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-07or-1009800000-2694fa0b23833f4e18ae Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0f6w-0004900000-1b2069cf1f63ff46c98d Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-03ka-1009600000-47b6ebc46fe3b6dfc849 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-006t-9016400000-78e9e6e2c0c5324acd84 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-00xr-0009000000-6a6cbcc7eb21624f9c60 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 243.3442967 predictedDarkChem Lite v0.1.0 [M-H]- 204.74129 predictedDeepCCS 1.0 (2019) [M+H]+ 242.3342967 predictedDarkChem Lite v0.1.0 [M+H]+ 207.09929 predictedDeepCCS 1.0 (2019) [M+Na]+ 242.4246967 predictedDarkChem Lite v0.1.0 [M+Na]+ 213.44122 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Zinc ion binding
- Specific Function
- Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
- Gene Name
- RARG
- Uniprot ID
- P13631
- Uniprot Name
- Retinoic acid receptor gamma
- Molecular Weight
- 50341.405 Da
References
- Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, Dreno B, Gamboa B, Jomard A, Luzy AP, Mauvais P, Mounier C, Pascau J, Pelisson I, Portal T, Rivier M, Rossio P, Thoreau E, Vial E, Voegel JJ: Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4. [Article]
- FDA Approved Drugs: Aklief® [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Agonist
- General Function
- Zinc ion binding
- Specific Function
- Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
- Gene Name
- RARB
- Uniprot ID
- P10826
- Uniprot Name
- Retinoic acid receptor beta
- Molecular Weight
- 50488.63 Da
References
- Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, Dreno B, Gamboa B, Jomard A, Luzy AP, Mauvais P, Mounier C, Pascau J, Pelisson I, Portal T, Rivier M, Rossio P, Thoreau E, Vial E, Voegel JJ: Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Agonist
- General Function
- Zinc ion binding
- Specific Function
- Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expressi...
- Gene Name
- RARA
- Uniprot ID
- P10276
- Uniprot Name
- Retinoic acid receptor alpha
- Molecular Weight
- 50770.805 Da
References
- Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, Dreno B, Gamboa B, Jomard A, Luzy AP, Mauvais P, Mounier C, Pascau J, Pelisson I, Portal T, Rivier M, Rossio P, Thoreau E, Vial E, Voegel JJ: Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018 Aug;179(2):442-456. doi: 10.1111/bjd.16719. Epub 2018 Jul 4. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drugs: Aklief® [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- 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 Drugs: Aklief® [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drugs: Aklief® [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drugs: Aklief® [Link]
Drug created at October 21, 2016 00:23 / Updated at April 23, 2024 11:38