Teriflunomide, sold under the brand name Aubagio, is the

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

leflunomide Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug ( DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibi ...

. Teriflunomide was investigated in the

Phase III clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

TEMSO as a medication for

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

(MS). The study was completed in July 2010. 2-year results were positive. However, the subsequent TENERE head-to-head comparison trial reported that "although permanent discontinuations f therapywere substantially less common among MS patients who received teriflunomide compared with

interferon beta-1a Interferon beta-1a (also interferon beta 1-alpha) is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified '' E. coli''. Some research indic ...

, relapses were more common with teriflunomide." The drug was approved for use in the United States in September 2012 and for use in the European Union in August 2013.

Mechanisms of action

Teriflunomide is an

immunomodulatory Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

drug inhibiting

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

de novo synthesis In chemistry, ''de novo'' synthesis () refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation. For example, nucleotides are not needed in the diet as ...

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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

. It also inhibits

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

enzymes, but only in high doses not clinically used.

Activation of leflunomide to teriflunomide

The branded drug teriflunomide is the main active ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' 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. Activation of leflunomide

"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

External links

* {{Portal bar , Medicine CYP1A2 inducers Anilides Enols Human drug metabolites Immunosuppressants Nitriles Sanofi Trifluoromethyl compounds

Mechanisms of action

Activation of leflunomide to teriflunomide

See also

References

External links