Eflornithine

Identification

Summary

Eflornithine is an ornithine decarboxylase inhibitor used to prevent relapse of high-risk neuroblastoma in pediatric and adult patients

Brand Names
Iwilfin, Vaniqa
Generic Name
Eflornithine
DrugBank Accession Number
DB06243
Background

Eflornithine is an irreversible ornithine decarboxylase inhibitor originally developed as a treatment for human African trypanosomiasis.6 Further research has also implicated ornithine decarboxylase in other conditions like facial hirsutism and cancer, especially when ornithine decarboxylase is highly upregulated in tumor cells.3,7 Additionally, ornithine decarboxylase is activated by c-myc or interacts with ras, both very well-known oncogenes, thus increasing the interest in targeting ornithine carboxylase as a potential cancer treatment.8

In 1960 and 2000, the FDA approved eflornithine under the brand names ORNIDYL and VANIQUA for the treatment of African trypanosomiasis and hirsutism, respectively, but has since been discontinued.5,13 Subsequently, on December 14, 2023, the FDA approved eflornithine again but under the brand name IWILFIN as an oral maintenance therapy to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy, including anti-GD2 immunotherapy. This approval is based on positive results obtained from a multi-site, single-arm, externally controlled study of children with high-risk neuroblastoma, where a 52% reduction in the risk of relapse and a 68% reduction in the risk of death were observed.12

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
Weight
Average: 182.171
Monoisotopic: 182.08668396
Chemical Formula
C6H12F2N2O2
Synonyms
  • (RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
  • 2-(difluoromethyl)ornithine
  • alpha-difluoromethylornithine
  • DFMO
  • Eflornithine
  • α-difluoromethylornithine
External IDs
  • BRN 2250529
  • HSDB 7923
  • MDL 71782
  • RFI 7178
  • RMI 71782

Pharmacology

Indication

Eflornithine is indicated to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy.9 It was also previously indicated for the treatment of female hirsutism and African trypanosomiasis but has since been discontinued.13

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prevention ofHigh risk neuroblastoma•••••••••••••••••• ••••••••••••••••••••• •• ••••• • ••••••• •••••••• •• ••••• ••••••••••• ••••••••••••• ••••••• ••••••••• •••••••• •••••••••••••••••••
Treatment ofMeningoencephalitic stage trypanosoma brucei gambiense infection••• ••••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Inhibition of polyamine synthesis by eflornithine restored the balance of the LIN28/Let-7 metabolic pathway, which is involved in the regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the oncogenic drivers MYCN and LIN28B in MYCN-amplified neuroblastoma. In vitro, eflornithine induced senescence and suppressed neurosphere formation in MYCN-amplified and MYCN non-amplified neuroblastoma cells, indicating a cytostatic effect. Treatment with eflornithine prevented or delayed tumor formation in mice injected with limiting dilutions of MYCN-amplified neuroblastoma cells.9

Additionally, polyamines are also involved in keratin synthesis, and inhibition of polyamines can decrease the proliferation of hair matrix cells and thus inhibit the anagen phase of hair production.4

Mechanism of action

Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. Polyamines are involved in the differentiation and proliferation of mammalian cells and are important for neoplastic transformation.9

TargetActionsOrganism
AOrnithine decarboxylase
inhibitor
Humans
Absorption

Following oral administrations of eflornithine, peak plasma concentrations of eflornithine (Cmax) were achieved (Tmax) 3.5 hours post-dosing. The Cmax and AUC (area under the concentration-time curve) of eflornithine were not affected by food (high fat and high calories). Administration of crushed tablets in a standard pudding admixture had no effect on eflornithine exposure (Cmax and AUC6h).9

The mean percutaneous absorption of eflornithine in women with unwanted facial hair, from a 13.9% w/w cream formulation, is < 1% of the radioactive dose, following either single or multiple doses under conditions of clinical use, that included shaving within 2 hours before radiolabeled dose application in addition to other forms of cutting or plucking and tweezing to remove facial hair. Steady state was reached within four days of twice-daily application. Following twice-daily application of 0.5 g of the cream (total dose 1.0 g/day; 139 mg as anhydrous eflornithine hydrochloride), under conditions of clinical use in women with unwanted facial hair (n=10), the steady-state Cmax, Ctrough and AUC12hr were approximately 10 ng/mL, 5 ng/mL, and 92 ng hr/mL, respectively, expressed in terms of the anhydrous free base of eflornithine hydrochloride. At steady state, the dose-normalized peak concentrations (Cmax) and the extent of daily systemic exposure (AUC) of eflornithine following twice-daily application of 0.5 g of the cream (total dose 1.0 g/day) is estimated to be approximately 100- and 60-fold lower, respectively, when compared to 370 mg/day once-daily oral doses.10

Volume of distribution

Eflornithine volume of distribution (Vz/F) is 24.3 L.9

Protein binding

Eflornithine does not specifically bind to human plasma proteins.9

Metabolism

This compound is not known to be metabolized and is primarily excreted unchanged in the urine.10

Route of elimination

This compound is not known to be metabolized and is primarily excreted unchanged in the urine.10

Half-life

The terminal plasma elimination half-life of eflornithine was 3.5 hours, and the apparent steady-state plasma half-life of eflornithine was approximately 8 hours.10,10

Clearance

The clearance (CL/F) of eflornithine is 5.3 L/h.10

Adverse Effects
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Toxicity

Based on findings from animal studies and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in embryo lethality at doses equivalent to the recommended human dose. There are no available data on the use of eflornithine in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.10

In a 2-year carcinogenicity study, once daily oral administration of eflornithine to female rats did not result in drug-related neoplasms at doses up to 600 mg/kg/day (10.5 times the human Cmax at the recommended clinical dose of 1152 ± 384 mg/m2).10

Eflornithine was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay.10

Dedicated fertility studies were not conducted with eflornithine.10

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
AmbroxolThe risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Bupivacaine.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Eflornithine hydrochloride4NH22NDW9H96020-91-6FJPAMFNRCFEGSD-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FlorexaCream4170 mg/30gTopicalPella Pharmaceuticals Co. ltd2012-02-09Not applicableUS flag
IwilfinTablet250 mg/1OralUSWM, LLC2024-01-15Not applicableUS flag
VaniqaCream139 mg/1gTopicalPhysicians Total Care, Inc.2004-07-26Not applicableUS flag
VaniqaCream11.5 %CutaneousAlmirall, S.A.2020-12-23Not applicableEU flag
VaniqaCream13.9 % w/wTopicalCipher Pharmaceuticals Inc.2005-11-01Not applicableCanada flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
FlorexaEflornithine hydrochloride (4170 mg/30g)CreamTopicalPella Pharmaceuticals Co. ltd2012-02-09Not applicableUS flag

Categories

ATC Codes
P01CX03 — EflornithineL01XX79 — EflornithineD11AX16 — Eflornithine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acids. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon).
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acids
Alternative Parents
Halogenated fatty acids / Branched fatty acids / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organofluorides / Organic oxides / Monoalkylamines / Hydrocarbon derivatives
show 2 more
Substituents
Aliphatic acyclic compound / Alkyl fluoride / Alkyl halide / Alpha-amino acid / Amine / Amino acid / Branched fatty acid / Carbonyl group / Carboxylic acid / Fatty acid
show 14 more
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
fluoroamino acid (CHEBI:41948)
Affected organisms
  • Humans and other mammals
  • Yeast, Molds, Trypanosomes
  • Trypanosoma brucei gambiense

Chemical Identifiers

UNII
ZQN1G5V6SR
CAS number
70052-12-9
InChI Key
VLCYCQAOQCDTCN-UHFFFAOYSA-N
InChI
InChI=1S/C6H12F2N2O2/c7-4(8)6(10,5(11)12)2-1-3-9/h4H,1-3,9-10H2,(H,11,12)
IUPAC Name
2,5-diamino-2-(difluoromethyl)pentanoic acid
SMILES
NCCCC(N)(C(F)F)C(O)=O

References

Synthesis Reference

https://www.google.com/patents/US4330559

General References
  1. Namazi MR: Hypothesis: the potential utility of topical eflornithine against cutaneous leishmaniasis. Indian J Dermatol Venereol Leprol. 2008 Mar-Apr;74(2):158-9. [Article]
  2. Priotto G, Pinoges L, Fursa IB, Burke B, Nicolay N, Grillet G, Hewison C, Balasegaram M: Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study. BMJ. 2008 Mar 29;336(7646):705-8. doi: 10.1136/bmj.39485.592674.BE. Epub 2008 Mar 5. [Article]
  3. Hoffmann R: A 4-month, open-label study evaluating the efficacy of eflornithine 11.5% cream in the treatment of unwanted facial hair in women using TrichoScan. Eur J Dermatol. 2008 Jan-Feb;18(1):65-70. Epub 2007 Dec 18. [Article]
  4. Jobanputra KS, Rajpal AV, Nagpur NG: Eflornithine. Indian J Dermatol Venereol Leprol. 2007 Sep-Oct;73(5):365-6. [Article]
  5. Kumar A, Naguib YW, Shi YC, Cui Z: A method to improve the efficacy of topical eflornithine hydrochloride cream. Drug Deliv. 2016 Jun;23(5):1495-501. doi: 10.3109/10717544.2014.951746. Epub 2014 Sep 3. [Article]
  6. Burri C, Brun R: Eflornithine for the treatment of human African trypanosomiasis. Parasitol Res. 2003 Jun;90 Supp 1:S49-52. doi: 10.1007/s00436-002-0766-5. Epub 2002 Dec 10. [Article]
  7. Alhosin M, Razvi SSI, Sheikh RA, Khan JA, Zamzami MA, Choudhry H: Thymoquinone and Difluoromethylornithine (DFMO) Synergistically Induce Apoptosis of Human Acute T Lymphoblastic Leukemia Jurkat Cells Through the Modulation of Epigenetic Pathways. Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820947489. doi: 10.1177/1533033820947489. [Article]
  8. Mohammed A, Janakiram NB, Madka V, Ritchie RL, Brewer M, Biddick L, Patlolla JM, Sadeghi M, Lightfoot S, Steele VE, Rao CV: Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling. Cancer Prev Res (Phila). 2014 Dec;7(12):1198-209. doi: 10.1158/1940-6207.CAPR-14-0176. Epub 2014 Sep 23. [Article]
  9. FDA Approved Drug Products: IWILFIN™ (eflornithine) tablets, for oral use [Link]
  10. FDA Approved Drug Products: VANIQA™ (eflornithine hydrochloride) Cream 13.9%, for topical use [Link]
  11. Eflornithine MSDS [Link]
  12. US WorldMeds Announces FDA Approval of IWILFIN™ (eflornithine) to Strengthen Fight Against Aggressive Childhood Cancer [Link]
  13. Iwilfin FDA Approval History [Link]
Human Metabolome Database
HMDB0242197
KEGG Drug
D07883
KEGG Compound
C07997
PubChem Compound
3009
PubChem Substance
310264864
ChemSpider
2902
BindingDB
50028197
RxNav
569
ChEBI
41948
ChEMBL
CHEMBL830
Drugs.com
Drugs.com Drug Page
Wikipedia
Eflornithine
FDA label
Download (243 KB)
MSDS
Download (48.1 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
4CompletedTreatmentHuman African Trypanosomiasis (HAT)1somestatusstop reasonjust information to hide
4CompletedTreatmentIdiopathic Hirsutism2somestatusstop reasonjust information to hide
4TerminatedTreatmentPseudofolliculitis Barbae1somestatusstop reasonjust information to hide
3Active Not RecruitingPreventionColorectal Neoplasms1somestatusstop reasonjust information to hide
3Active Not RecruitingTreatmentAnaplastic Astrocytoma (AA) / Recurrent Anaplastic Astrocytoma1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CreamTopical13.9 %
CreamTopical
CreamTopical4170 mg/30g
TabletOral250 mg/1
CreamCutaneous
CreamCutaneous11.5 %
CreamTopical13.9 % w/w
CreamTopical139 mg/1g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5648394No1997-07-152014-07-15US flag
CA2158041No2001-04-032013-05-27Canada flag
US4330559No1982-05-181997-07-11US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)347 ºChttps://www.chemicalbook.com/msds/eflornithine-hydrochloride.pdf
water solubility>10 mg/mLhttps://www.chemicalbook.com/msds/eflornithine-hydrochloride.pdf
Predicted Properties
PropertyValueSource
Water Solubility50.0 mg/mLALOGPS
logP-2ALOGPS
logP-2.9Chemaxon
logS-0.56ALOGPS
pKa (Strongest Acidic)2.19Chemaxon
pKa (Strongest Basic)10.2Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area89.34 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity37.73 m3·mol-1Chemaxon
Polarizability15.8 Å3Chemaxon
Number of Rings0Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-001r-9200000000-bd932d11510b4f6052c3
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-001i-0900000000-df91c4b4acdcbe7cee41
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00xr-0900000000-9a7e6cedd31e8d4feff3
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-0900000000-83896c5cd4b28a1aeb5b
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00di-4900000000-3d4818a740257594aecb
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00e9-9300000000-3f52c4f986a5917af0ff
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-70bd7e53aa3a2796998b
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-01b9-0900000000-beac1332c3de78109e4c
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0900000000-59058c1476c84420febc
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-4900000000-c1cedb3be0f32e6526cc
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gb9-5900000000-7fc262271a2df5e3349b
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-9100000000-b889722a014c710c7593
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-131.75923
predicted
DeepCCS 1.0 (2019)
[M+H]+135.59212
predicted
DeepCCS 1.0 (2019)
[M+Na]+144.50359
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein homodimerization activity
Specific Function
Key enzyme of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine.
Gene Name
ODC1
Uniprot ID
P11926
Uniprot Name
Ornithine decarboxylase
Molecular Weight
51147.73 Da
References
  1. Poulin R, Lu L, Ackermann B, Bey P, Pegg AE: Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites. J Biol Chem. 1992 Jan 5;267(1):150-8. [Article]
  2. FDA Approved Drug Products: IWILFIN™ (eflornithine) tablets, for oral use [Link]

Drug created at March 19, 2008 16:19 / Updated at July 19, 2024 07:26