Teriflunomide

Adverse effects

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

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.

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.

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.

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.

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

References

References

1. (11 September 2019). "Teriflunomide (Aubagio) Use During Pregnancy".
2. Anvisa. (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
3. (21 November 2023). "Aubagio- teriflunomide tablet, film coated".
4. (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.
5. {{ClinicalTrialsGov. NCT00134563. Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
6. (15 October 2010). "Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". Genetic Engineering & Biotechnology News.
7. (4 June 2012). "Teriflunomide Modest Help but Safe for MS". Joint meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
8. (5 November 2012). "Drug Approval Package: Aubagio (teriflunomide) Tablets NDA #202992".
9. "FDA approves new multiple sclerosis treatment Aubagio". U.S. [[Food and Drug Administration]] (FDA).
10. (26 August 2013). "Aubagio EPAR".
11. (13 March 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung.
12. (28 May 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News.
13. (November 2000). "Leflunomide: mode of action in the treatment of rheumatoid arthritis". Annals of the Rheumatic Diseases.
14. "Assessment report. AUBAGIO (international non-proprietary name: teriflunomide). Procedure No. EMEA/H/C/002514/0000".
15. (2002). "Clinical pharmacokinetics of leflunomide". Clinical Pharmacokinetics.
16. "Clinical Pharmacology/Biopharmaceutics Review. Product: Arava (leflunomide tablets). Application Number: NDA 20905".
17. "Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)". European Medicines Agency.