Clinical Drug Experience Knowledgebase

Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries. Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Leflunomide is rapidly metabolized to its active form, teriflunomide (A77 1726). Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. Teriflunomide is also an inhibitor of CYP2C8 in vivo. In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide.   ^NCATS