Teriflunomide

Teriflunomide (trade name Aubagio, marketed by Sanofi) is the active metabolite of leflunomide.[1] Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] 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."[4] The drug was approved by the FDA on September 13, 2012[5] and in the European Union on August 26, 2013.[6]

Teriflunomide
Clinical data
Trade namesAubagio
Other namesA77 1726
License data
Pregnancy
category
  • US: X (Contraindicated)
    Routes of
    administration    		Oral (tablets)
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding>99.3%
    Elimination half-life2 weeks
    ExcretionBiliary/fecal, renal
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.170.077
    Chemical and physical data
    FormulaC12H9F3N2O2
    Molar mass270.207 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    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.[7]

    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.[8]

    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.[9]

    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.[10]

    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.[11][12]

    "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."[10] Because of this, EMA initially had not considered teriflunomide being a new active substance.[13]

    See also

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

    References
    1. 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.
    2. ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
    3. "Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". 15 Oct 2010.
    4. Gever J (June 4, 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 June 4, 2012.
    5. "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. Retrieved 2012-09-14.
    6. EU authorisation details, EMA, retrieved 2014-04-29
    7. Spreitzer H (March 13, 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung (in German) (6/2006).
    8. Vollmer T (May 28, 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News (May 28, 2009).
    9. 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.
    10. Melchiorri D, Barbara vZ, Romaldas M, Nela V, Karsten BS, Ian H, Robert H, Harald E, Pierre D. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000" (PDF). European Medicines Agency. European Medicines Agency. p. 119. Retrieved 5 June 2015.
    11. Rozman B (2002). "Clinical pharmacokinetics of leflunomide". Clinical Pharmacokinetics. 41 (6): 421–30. doi:10.2165/00003088-200241060-00003. PMID 12074690.
    12. "Clinical Pharmacology/Biopharmaceutics Review. Product: ARAVA (leflunomide tablets). Application Number: NDA 20905" (PDF). U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Retrieved 15 April 2016.
    13. "Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)" (PDF). European Medicines Agency. Retrieved 15 April 2016.
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