Teriflunomide

From WikiProjectMed
Jump to navigation Jump to search
Teriflunomide
Teriflunomide structure.svg
Ball-and-stick model of the teriflunomide molecule
Names
Trade namesAubagio
Other namesA77 1726
  • (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
Clinical data
Drug classPyrimidine synthesis inhibitor[1]
Main usesMultiple sclerosis (MS)[2]
Side effectsHeadache, diarrhea, liver problems, nausea, hair loss[3]
Pregnancy
category
  • AU: X (High risk)[4]
  • US: N (Not classified yet)[4]
  • Contraindicated[4]
Routes of
use
By mouth
Typical dose14 mg per day[1]
External links
AHFS/Drugs.comMonograph
US NLMTeriflunomide
MedlinePlusa613010
Legal
License data
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetics
Protein binding>99.3%
Elimination half-life2 weeks
ExcretionBile duct/fecal, kidney
Chemical and physical data
FormulaC12H9F3N2O2
Molar mass270.211 g·mol−1
3D model (JSmol)
  • 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 a medication used to treat multiple sclerosis (MS); specifically relapsing-remitting MS.[2][3] In Scotland it is used as a second line treatment to interferon beta and glatiramer.[1] It is taken by mouth.[2]

Common side effects include headache, diarrhea, liver problems, nausea, and hair loss.[3] Other side effects may include liver failure, peripheral neuropathy, and interstitial lung disease.[2] Use in the two years before or during pregnancy may harm the baby.[1] It is a pyrimidine synthesis inhibitor.[1] While how it works is not entirely clear, it is believed to decrease the number of lymphocytes.[3] It is the active metabolite of leflunomide.[2]

Teriflunomide was approved for medical use in the United States in 2012 and and Europe 2013.[3][2] In the United Kingdom it costs the NHS about 1,100 pounds per month.[1] This amount in the United States costs about 8,400 USD as of 2021.[5]

Medical uses

Teriflunomide was investigated in the phase III clinical trial TEMSO as a medication for multiple sclerosis (MS).[6] However, a subsequent comparison trial reported that although permanent discontinuations were less common among people with MS who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide.[7]

Dosage

It is taken at a dose of 14 mg once per day.[1]

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.[8]

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.[9]

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.[10]

Activation of leflunomide

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.[11]

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.[12][13]

"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."[11] Because of this, EMA initially had not considered teriflunomide being a new active substance.[14]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 905. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
  2. 2.0 2.1 2.2 2.3 2.4 2.5 "Teriflunomide Monograph for Professionals". Drugs.com. Retrieved 29 September 2021.
  3. 3.0 3.1 3.2 3.3 3.4 "Aubagio EPAR". European Medicines Agency (EMA). 26 February 2020. Retrieved 1 March 2020.
  4. 4.0 4.1 4.2 "Teriflunomide (Aubagio) Use During Pregnancy". Drugs.com. 11 September 2019. Retrieved 2 March 2020.
  5. "Aubagio Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 29 September 2021.
  6. ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  7. 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.
  8. Spreitzer H (March 13, 2006). "Neue Wirkstoffe - Teriflunomid". Österreichische Apothekerzeitung (in German) (6/2006).CS1 maint: unrecognized language (link)
  9. Vollmer T (May 28, 2009). "MS Therapies in the Pipeline: Teriflunomide". EMS News (May 28, 2009).
  10. 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.
  11. 11.0 11.1 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.
  12. Rozman B (2002). "Clinical pharmacokinetics of leflunomide". Clinical Pharmacokinetics. 41 (6): 421–30. doi:10.2165/00003088-200241060-00003. PMID 12074690. S2CID 33745823.
  13. "Clinical Pharmacology/Biopharmaceutics Review. Product: Arava (leflunomide tablets). Application Number: NDA 20905" (PDF). U.S. Food and Drug Administration (FDA). Retrieved 15 April 2016.
  14. "Summary of Opinion (Initial Authorisation): Aubagio (teriflunomide)" (PDF). European Medicines Agency. Retrieved 15 April 2016.

External links

External sites:
Identifiers: