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- Approved, Withdrawn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
Structure for Eflornithine (DB06243)
- 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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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of High risk neuroblastoma •••••••••••• •••••• ••••••••• •••••••••••• •• ••••• • ••••••• •••••••• •• ••••• ••••••••••• ••••••••••••• ••••••• ••••••••• •••••••• ••••••••••••• •••••• Treatment of Meningoencephalitic stage trypanosoma brucei gambiense infection ••• ••••• ••••••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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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
Target Actions Organism AOrnithine decarboxylase inhibitorHumans - 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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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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 softwareAmbroxol The risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Ambroxol. Articaine The risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Articaine. Benzocaine The risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Benzocaine. Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Benzyl alcohol. Bupivacaine The risk or severity of methemoglobinemia can be increased when Eflornithine is combined with Bupivacaine. - Food Interactions
- Take with or without food.
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.- Product Ingredients
Ingredient UNII CAS InChI Key Eflornithine hydrochloride 4NH22NDW9H 96020-91-6 FJPAMFNRCFEGSD-UHFFFAOYSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Florexa Cream 4170 mg/30g Topical Pella Pharmaceuticals Co. ltd 2012-02-09 Not applicable US 
Iwilfin Tablet 250 mg/1 Oral USWM, LLC 2024-01-15 Not applicable US Vaniqa Cream 11.5 % Cutaneous Almirall, S.A. 2020-12-23 Not applicable EU 
Vaniqa Cream 13.9 % w/w Topical Cipher Pharmaceuticals Inc. 2005-11-01 Not applicable Canada 
Vaniqa Cream 139 mg/1g Topical Physicians Total Care, Inc. 2004-07-26 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Florexa Eflornithine hydrochloride (4170 mg/30g) Cream Topical Pella Pharmaceuticals Co. ltd 2012-02-09 Not applicable US
Categories
- ATC Codes
- P01CX03 — Eflornithine
- P01CX — Other agents against leishmaniasis and trypanosomiasis
- P01C — AGENTS AGAINST LEISHMANIASIS AND TRYPANOSOMIASIS
- P01 — ANTIPROTOZOALS
- P — ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS
- Drug Categories
- Agents Against Leishmaniasis and Trypanosomiasis
- Amino Acids
- Amino Acids, Basic
- Amino Acids, Diamino
- Amino Acids, Peptides, and Proteins
- Anti-Infective Agents
- Antineoplastic Agents
- Antiparasitic Agents
- Antiparasitic Products, Insecticides and Repellents
- Antiprotozoals
- Decarboxylase Inhibitor
- Decarboxylase Inhibitors
- Dermatologicals
- Enzyme Inhibitors
- Misc. Skin and Mucous Membrane Agents
- Ornithine Decarboxylase Inhibitors
- Trypanocidal Agents
- 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
- 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]
- 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]
- 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]
- Jobanputra KS, Rajpal AV, Nagpur NG: Eflornithine. Indian J Dermatol Venereol Leprol. 2007 Sep-Oct;73(5):365-6. [Article]
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: IWILFIN™ (eflornithine) tablets, for oral use [Link]
- FDA Approved Drug Products: VANIQA™ (eflornithine hydrochloride) Cream 13.9%, for topical use [Link]
- Eflornithine MSDS [Link]
- US WorldMeds Announces FDA Approval of IWILFIN™ (eflornithine) to Strengthen Fight Against Aggressive Childhood Cancer [Link]
- Iwilfin FDA Approval History [Link]
- External Links
- Human Metabolome Database
- HMDB0242197
- KEGG Drug
- D07883
- KEGG Compound
- C07997
- PubChem Compound
- 3009
- PubChem Substance
- 310264864
- ChemSpider
- 2902
- BindingDB
- 50028197
- 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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Human African Trypanosomiasis (HAT) 1 4 Completed Treatment Idiopathic Hirsutism 2 4 Terminated Treatment Pseudofolliculitis Barbae 1 3 Active Not Recruiting Prevention Colorectal Neoplasms 1 3 Active Not Recruiting Treatment Anaplastic Astrocytoma (AA) / Recurrent Anaplastic Astrocytoma 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cream Topical 13.9 % Cream Topical Cream Topical 4170 mg/30g Tablet Oral 250 mg/1 Cream Cutaneous Cream Cutaneous 11.5 % Cream Topical 13.9 % w/w Cream Topical 139 mg/1g - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5648394 No 1997-07-15 2014-07-15 US CA2158041 No 2001-04-03 2013-05-27 Canada US4330559 No 1982-05-18 1997-07-11 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 347 ºC https://www.chemicalbook.com/msds/eflornithine-hydrochloride.pdf water solubility >10 mg/mL https://www.chemicalbook.com/msds/eflornithine-hydrochloride.pdf - Predicted Properties
Property Value Source Water Solubility 50.0 mg/mL ALOGPS logP -2 ALOGPS logP -2.9 Chemaxon logS -0.56 ALOGPS pKa (Strongest Acidic) 2.19 Chemaxon pKa (Strongest Basic) 10.2 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 89.34 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 37.73 m3·mol-1 Chemaxon Polarizability 15.8 Å3 Chemaxon Number of Rings 0 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
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 131.75923 predictedDeepCCS 1.0 (2019) [M+H]+ 135.59212 predictedDeepCCS 1.0 (2019) [M+Na]+ 144.50359 predictedDeepCCS 1.0 (2019)
Targets
- 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
- 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]
- FDA Approved Drug Products: IWILFIN™ (eflornithine) tablets, for oral use [Link]
Drug created at March 19, 2008 16:19 / Updated at February 20, 2024 23:55