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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 inhibitor that works by inhibiting dihydroorotate dehydrogenase.
The concomitant use of methotrexate, in particular, may lead to severe or even fatal liver-damage or hepatotoxicity. Seventy-five percent of all cases of severe liver damage reported until early 2001 were seen under combined drug therapy leflunomide plus methotrexate. However, some studies have shown that the combination of methotrexate and leflunomide in patients with rheumatoid arthritis gave better results than either drug alone.
The inhibition of human DHODH by teriflunomide, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA). Teriflunomide also inhibits several tyrosine kinases. Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their ribonucleotides by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis. Teriflunomide also has antiviral effects against numerous viruses including cytomegalovirus, HSV1 and the BK virus, which it achieves by inhibiting viral replication by interfering with nucleocapsid tegumentation and hence virion assembly.
"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, the European Medicines Agency (EMA) initially had not considered teriflunomide to be a new active substance.
Pharmacology
Mechanism of action
Leflunomide is an drug that achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of uridine monophosphate (rUMP), which is required for the synthesis of DNA and RNA. Hence, leflunomide inhibits the reproduction of rapidly dividing cells, especially lymphocytes.
Pharmacokinetics
It has an oral bioavailability of 80%, protein binding of >99%, metabolism sites of the GI mucosa and liver, volume of distribution (Vd) of 0.13 L/kg, elimination half-life of 14–18 days and excretion routes of faeces (48%) and urine (43%).
Leflunomide metabolism
Teriflunomide is the main active in vivo metabolite of 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. Upon oral administration of leflunomide in vivo, the isoxazole ring of leflunomide is opened and teriflunomide is formed.
Further reading
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