A Comprehensive Monograph on Leflunomide (DB01097)

1.0 Executive Summary

Leflunomide is a pivotal isoxazole-derivative, disease-modifying antirheumatic drug (DMARD) that represents a significant therapeutic option in the management of autoimmune inflammatory conditions.[1] It functions as a prodrug, undergoing rapid and extensive conversion following oral administration to its pharmacologically active metabolite, A77 1726, also known as teriflunomide.[3] Teriflunomide is responsible for virtually all of the drug's in-vivo activity and exerts its primary therapeutic effect through the selective and reversible inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).[3] This targeted mechanism interrupts the

de novo pyrimidine synthesis pathway, a metabolic route that is critically essential for the proliferation of activated T and B lymphocytes that drive autoimmune pathology. By depriving these specific cells of the nucleotides required for DNA and RNA synthesis, leflunomide induces a G1 phase cell cycle arrest, resulting in a targeted, cytostatic (proliferation-inhibiting) immunomodulatory effect rather than a broadly cytotoxic one.[3]

Leflunomide is approved by major regulatory bodies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), for the treatment of active rheumatoid arthritis (RA) and active psoriatic arthritis (PsA).[3] In these conditions, it has demonstrated efficacy in reducing signs and symptoms, improving physical function, and, crucially, inhibiting the progression of structural joint damage.[3] Beyond its approved indications, leflunomide has found notable off-label application in the management of solid organ transplant rejection, for which it holds an FDA orphan drug designation, and as an investigational therapy for lupus nephritis.[3]