Leflunomide

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Leflunomide
Leflunomide.svg
Leflunomide ball-and-stick model.png
Systematic (IUPAC) name
5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide
Clinical data
Trade names Arava, Arabloc, Lunava, Repso, Elafra
AHFS/Drugs.com monograph
MedlinePlus a600032
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
Legal status
Routes of
administration		 Oral (tablets)
Pharmacokinetic data
Bioavailability 80%[1]
Protein binding >99%[1]
Metabolism GI mucosa and liver[1]
Biological half-life 14–18 days[1]
Excretion Faeces (48%), urine (43%)[1]
Identifiers
CAS Number 75706-12-6 YesY
ATC code L04AA13 (WHO)
PubChem CID: 3899
IUPHAR/BPS 6825
DrugBank DB01097 YesY
ChemSpider 3762 YesY
UNII G162GK9U4W YesY
KEGG D00749 YesY
ChEBI CHEBI:6402 YesY
ChEMBL CHEMBL960 YesY
Chemical data
Formula C12H9F3N2O2
Molecular mass 270.207 g/mol
  • O=C(Nc1ccc(cc1)C(F)(F)F)c2c(onc2)C
  • InChI=1S/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18) YesY
  • Key:VHOGYURTWQBHIL-UHFFFAOYSA-N YesY
  (verify)

Leflunomide (original brand name Arava) is an immunosuppressive disease-modifying antirheumatic drug (DMARD),[2] used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor.[3]

Bottle of Leflunomide (Arava) and tablet

Medical use

Rheumatoid arthritis and psoriatic arthritis are the only indications that have received regulatory approval.[1][4] Clinical studies regarding the following diseases have been conducted:[5]

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Side effects

Its principle dose-limiting side effects are liver damage, lung disease and immunosuppression.[19] The most common side effects (occurring in >1% of those treated with it) are, in approximately descending order of frequency:[1][4][20][21][22][23][24] diarrhea, respiratory tract infections, hair loss, high blood pressure, rash, nausea, bronchitis, headache, abdominal pain, abnormal liver function tests, back pain, indigestion, urinary tract infection, dizziness, infection, joint disorder, itchiness, weight loss, loss of appetite, cough, gastroenteritis, pharyngitis, stomatitis, tenosynovitis, vomiting, weakness, allergic reaction, chest pain, dry skin, eczema, paraesthesia, pneumonia, rhinitis, synovitis, cholelithiasis and shortness of breath. Whereas uncommon side effects (occurring in 0.1-1% of those treated with the drug) include:[4] constipation, oral thrush, stomatitis, taste disturbance, thrombocytopenia and hives. Rarely (in 0.1% of those treated with it) it can cause:[4] anaphylaxis, angiooedema, anaemia, agranulocytosis, eosinophilia, leucopenia, pancytopenia, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, cutaneous lupus erythematosus, severe infection, interstitial lung disease, cirrhosis and liver failure.

Contraindications

Contraindications include:[1]

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  • Pregnancy, women of childbearing potential (unless contraception used)
  • Liver disease, hepatitis B/C seropositive
  • Active serious infections
  • Hypersensitivity

Interactions

Other immunomodulatory treatments should be avoided due to the potential for additive immunosuppressant effects, or in the case of immunostimulants like echinacea or astragalus, reduced therapeutic effects.[1] Likewise live vaccines (like haemophilus influenzae type b vaccine and yellow fever vaccines) should be avoided due to the potential for severe infection due to the immunosuppressive nature of the treatment.[1]

The concomitant use of methotrexate, in particular, may lead to severe or even fatal liver-damage or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate.[25] However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.[25]

Mechanism of action

Leflunomide is an immunomodulatory drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA. Hence, leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes.[19]

The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA).[26] Teriflunomide also inhibits several tyrosine kinases.[19] Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis.[26] Teriflunomide also has antiviral effects against numerous viruses including CMV, HSV1 and the BK virus, which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly.[19]

Pharmacokinetics

It has an oral bioavailability of 80%, protein binding of >99%, metabolism sites of the GI mucosa and liver, volume of distribution (Vd) of 0.13 L/kg, elimination half-life of 14–18 days and excretion routes of faeces (48%) and urine (43%).[1][19][20]

Leflunomide metabolism and similarity to teriflunomide

Teriflunomide is the main active in vivo metabolite of leflunomide. Upon administration of leflunomide, 70% of the drug administered converts into teriflunomide. The only difference between the molecules is the opening of the isoxazole ring. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[27]

Teriflunomide is the active metabolite of leflunomide, responsible for its therapeutic actions. It results from the reaction of isoxazole ring opening, which occurs in vivo. Teriflunomide then can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z-enol being the most stable and therefore most predominant form.[28][29]

“Regardless of the substance administered (leflunomide or teriflunomide), it is the same molecule (teriflunomide)—the one exerting the pharmacological, immunological or metabolic action in view of restoring, correcting or modifying physiological functions, and does not present, in clinical use, a new chemical entity to patients.”[27] Because of this, EMA had not considered teriflunomide being a new active substance.[30]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 4.3 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ http://clinicaltrials.gov/ct2/results?term=Leflunomide
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ 20.0 20.1 Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ 25.0 25.1 Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ 26.0 26.1 Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ 27.0 27.1 Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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