Teriflunomide

Teriflunomide
Ball-and-stick model of the teriflunomide molecule
Clinical data
Trade namesAubagio
Other namesA77 1726
AHFS/Drugs.comMonograph
MedlinePlusa613010
License data
Pregnancy
category
  • AU: X (High risk)[1]
  • Contraindicated[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)[3]
  • US: WARNING[2]Rx-only
  • EU: Rx-only
Pharmacokinetic data
Protein binding>99.3%
Elimination half-life2 weeks
ExcretionBile duct/fecal, kidney
Identifiers
  • (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
CAS Number
  • 163451-81-8 ☒N
PubChem CID
  • 54684141
IUPHAR/BPS
  • 6844
DrugBank
  • DB08880 checkY
ChemSpider
  • 16737143 checkY
UNII
  • 1C058IKG3B
KEGG
  • D10172 ☒N
ChEBI
  • CHEBI:68540 ☒N
ChEMBL
  • ChEMBL973 checkY
CompTox Dashboard (EPA)
  • DTXSID80893457
ECHA InfoCard100.170.077
Chemical and physical data
FormulaC12H9F3N2O2
Molar mass270.211 g·mol−1
3D model (JSmol)
  • Interactive image
  • O=C(Nc1ccc(cc1)C(F)(F)F)C(/C#N)=C(/C)O
  • InChI=1S/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,18H,1H3,(H,17,19)/b10-7- checkY
  • Key:UTNUDOFZCWSZMS-YFHOEESVSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Teriflunomide, sold under the brand name Aubagio, is the active metabolite of leflunomide.[4] Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[5] 2-year results were positive.[6] However, the subsequent TENERE head-to-head comparison trial reported that "although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide."[7] The drug was approved for use in the United States in September 2012[8][9] and for use in the European Union in August 2013.[10]

Adverse effects

The US Food and Drug Administration's prescribing information warns of potential hepatotoxicity (liver injury including liver failure) and teratogenicity (birth defects).[11] Elavated ALT enzyme levels is the most common side effect (≥10% and ≥2% over placebo).[11]

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[12]

Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[13]

It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[14]

Activation of leflunomide to teriflunomide

The branded drug teriflunomide is the main active in vivo metabolite of the generically available 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. This is considered a simple structural modification and a technically simple one-step synthetic transformation. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.[15]

Teriflunomide is the only active metabolite of leflunomide, completely 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), the Z-enol being the most stable and therefore most predominant form.[16][17]

"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."[15] Because of this, EMA initially had not considered teriflunomide being a new active substance.[18]

See also

See leflunomide for information on pharmacokinetics, side effects, contraindications and other data.

References

  1. ^ a b "Teriflunomide (Aubagio) Use During Pregnancy". Drugs.com. 11 September 2019. Retrieved 2 March 2020.
  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  3. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. ^ Magne D, Mézin F, Palmer G, Guerne PA (November 2006). "The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha". Inflammation Research. 55 (11): 469–75. doi:10.1007/s00011-006-5196-x. PMID 17122964. S2CID 47034503.
  5. ^ Clinical trial number NCT00134563 for "Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)" at ClinicalTrials.gov
  6. ^ "Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". Genetic Engineering & Biotechnology News. 15 October 2010.
  7. ^ Gever J (4 June 2012). "Teriflunomide Modest Help but Safe for MS". medpage. Joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis. Retrieved 4 June 2012.
  8. ^ "Drug Approval Package: Aubagio (teriflunomide) Tablets NDA #202992". U.S. Food and Drug Administration (FDA). 5 November 2012. Retrieved 1 March 2020.
  9. ^ "FDA approves new multiple sclerosis treatment Aubagio" (Press release). U.S. Food and Drug Administration (FDA). Archived from the original on 13 September 2012. Retrieved 14 September 2012.
  10. ^ "Aubagio EPAR". European Medicines Agency (EMA). 26 February 2020. Retrieved 1 March 2020.
  11. ^ a b "Highlights of Prescribing Information" (PDF). US Food and Drug Association. Retrieved 24 February 2024.
  12. ^ Spreitzer H (13 March 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung (in German) (6/2006).
  13. ^ Vollmer T (28 May 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News (May 28, 2009).
  14. ^ Breedveld FC, Dayer JM (November 2000). "Leflunomide: mode of action in the treatment of rheumatoid arthritis". Annals of the Rheumatic Diseases. 59 (11): 841–9. doi:10.1136/ard.59.11.841. PMC 1753034. PMID 11053058.
  15. ^ a b Melchiorri D, van Zwieten-Boot B, Romaldas M, Nela V, Karsten BS, Ian H, et al. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000" (PDF). European Medicines Agency. p. 119. Archived from the original (PDF) on 17 July 2015. Retrieved 5 June 2015.
  16. ^ Rozman B (2002). "Clinical pharmacokinetics of leflunomide". Clinical Pharmacokinetics. 41 (6): 421–30. doi:10.2165/00003088-200241060-00003. PMID 12074690. S2CID 33745823.
  17. ^ "Clinical Pharmacology/Biopharmaceutics Review. Product: Arava (leflunomide tablets). Application Number: NDA 20905" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 15 April 2016.
  18. ^ "Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)" (PDF). European Medicines Agency. Archived from the original (PDF) on 13 March 2016. Retrieved 15 April 2016.
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