Teriflunomide

Teriflunomide, sold under the brand name Aubagio, is the active metabolite of leflunomide.^[5] Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.^[6] 2-year results were positive.^[7] 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."^[8] The drug was approved for use in the United States in September 2012^[9][10] and for use in the European Union in August 2013.^[4]

Teriflunomide

Clinical data
Trade names	Aubagio
Other names	A77 1726
AHFS/Drugs.com	Monograph
MedlinePlus	a613010
License data	US DailyMed: Teriflunomide
Pregnancy category	AU: X (High risk)[1] Contraindicated[1]
Routes of administration	By mouth
ATC code	L04AK02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[2] US: ℞-only[3] EU: Rx-only[4]
Pharmacokinetic data
Protein binding	>99.3%
Elimination half-life	2 weeks
Excretion	Bile duct/fecal, kidney
Identifiers
IUPAC name (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 Y
ChemSpider	16737143 Y
UNII	1C058IKG3B
KEGG	D10172 N
ChEBI	CHEBI:68540 N
ChEMBL	ChEMBL973 Y
CompTox Dashboard (EPA)	DTXSID80893457
ECHA InfoCard	100.170.077
Chemical and physical data
Formula	C12H9F3N2O2
Molar mass	270.211 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(Nc1ccc(cc1)C(F)(F)F)C(/C#N)=C(/C)O
InChI 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- Y Key:UTNUDOFZCWSZMS-YFHOEESVSA-N Y
NY (what is this?)  (verify)

Adverse effects

Further information: leflunomide

The US Food and Drug Administration's prescribing information warns of potential hepatotoxicity (liver injury including liver failure) and teratogenicity (birth defects).^[3] Elavated ALT enzyme levels is the most common side effect (≥10% and ≥2% over placebo).^[3]

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.^[11]

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.^[12]

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.^[13]

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.^[14]

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.^[15][16]

"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."^[14] Because of this, EMA initially had not considered teriflunomide being a new active substance.^[17]