Trifarotene

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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
ARetinoic acid receptor gamma
agonist
Humans
URetinoic acid receptor beta
agonist
Humans
URetinoic acid receptor alpha
agonist
Humans
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
Adverseeffects
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Toxicity

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

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AkliefCream50 mcg / gTopicalGalderma2019-11-28Not applicableCanada flag
AkliefCream50 ug/1gTopicalGalderma Laboratories, L.P.2019-10-04Not applicableUS flag

Categories

ATC Codes
D10AD06 — Trifarotene
Drug Categories
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
  1. 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]
  2. Balak DMW: Topical trifarotene: a new retinoid. Br J Dermatol. 2018 Aug;179(2):231-232. doi: 10.1111/bjd.16733. [Article]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Approved Drugs: Aklief® [Link]
PubChem Compound
11518241
PubChem Substance
347828982
ChemSpider
9693029
RxNav
2205637
ChEMBL
CHEMBL3707313
Wikipedia
Trifarotene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAcne Vulgaris1
4RecruitingTreatmentAcne Vulgaris1
3CompletedTreatmentAcne Vulgaris4
2CompletedTreatmentAcne Vulgaris1
2TerminatedTreatmentLamellar Ichthyosis1
1CompletedTreatmentMalignant Lymphomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CreamTopical50 ug/1g
CreamTopical50 mcg / g
CreamTopical
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8470871No2013-06-252025-12-21US flag
US9084778No2015-07-212033-05-30US flag
US8227507No2012-07-242025-12-21US flag
US7807708No2010-10-052026-10-01US flag
US9498465No2013-05-302033-05-30US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)245CFDA Label
pKa5.69 (pKa1)FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.000945 mg/mLALOGPS
logP6.12ALOGPS
logP5.15ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)3.97ChemAxon
pKa (Strongest Basic)4.75ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area70 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity136.98 m3·mol-1ChemAxon
Polarizability53.11 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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insights and accelerate drug research.
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Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
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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
  1. 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]
  2. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. FDA Approved Drugs: Aklief® [Link]

Drug created on October 21, 2016 00:23 / Updated on September 25, 2021 16:29