Leflunomide

Mechanism

💊 Common Business Names

Arava, Leflunomide, Leflunex, Filartros, Arava-Gen.

🔬 Pharmacological Group

Immunomodulator, inhibitor of pyrimidine synthesis. csDMARD derived from isoxazole.

Mechanism of Action

Leflunomide is a prodrug that undergoes immediate conversion to its active metabolite in vivo:

• Active Metabolite Teriflunomide (A77 1726): It is generated by opening of the isoxazole ring in the intestinal tract and liver in a non-enzymatic manner rapidly after administration.
• Selective inhibition of Dihydroorotate Dehydrogenase (DHODH): The metabolite A77 1726 binds and potently inhibits DHODH, a key mitochondrial enzyme in the de novo synthesis of uridine monophosphate (UMP), a common precursor of pyrimidine nucleotides.
• Blocking the Clonal Expansion of Activated T Lymphocytes:
  1. Salvage Pathway vs. De Novo Synthesis: Resting cells obtain pyrimidines through the salvage pathway. However, activated T and B lymphocytes in rheumatoid synovitis must multiply their pool of pyrimidines up to 8 times, depending strictly on the de novo synthesis pathway.
  2. Stop in G1 Phase of the Cell Cycle: As DHODH is blocked, activated lymphocytes suffer depletion of UMP, stopping their mitotic cycle in the G1 phase in a stable manner and stopping inflammatory clonal expansion.
  3. Inhibition of Cell Migration: It is associated with the reduction of endothelial adhesion molecules and interference in signaling pathways activated by cytokines such as IL-17.

Pharmacokinetics

Key Pharmacokinetics

Leflunomide Accelerated Elimination Protocol (Washout)

Due to enterohepatic recirculation and high-affinity binding to albumin, spontaneous clearance of leflunomide to achieve undetectable concentrations (<0.02 mg/L) may take up to 2 years. If emergency removal is required due to severe toxicity, pregnancy or desire for conception, the flushing protocol should be applied: administer Cholestyramine (8 grams orally 3 times a day for a total of 11 consecutive days) or activated charcoal. Cholestyramine binds to the active metabolite excreted in the bile in the lumen of the duodenum, interrupting the absorption circuit and managing to clear the drug in days.

Indicators and dose

Dosage and Adjustment

• Adults:
  • Loading Dose (Optional, commonly omitted in routine clinical rheumatology to avoid severe diarrhea): 100 mg orally once a day for 3 consecutive days.
  • Maintenance Dose: 10 mg to 20 mg orally once a day.
• Pediatrics: Not generally recommended in children under 18 years of age due to lack of systematic studies in the child population.
• Adjustment in Kidney Failure:
  • Cl_cr ≥ 30 mL/min: No adjustment is required for short therapies, monitoring potassium and arterial hypertension.
  • Cl_cr < 30 mL/min: Use with extreme caution due to the high protein binding that may be altered in uremia, reducing the dose to a maximum of 10 mg every other day.
• Adjustment in Liver Failure: Absolutely contraindicated in pre-existing liver failure due to the marked hepatic clearance of phase I and conjugation.

Security

Contraindications

• Absolute: Moderate or severe liver failure (Child-Pugh B or C) or uncontrolled elevated transaminases; severe active immunodeficiency; previous severe myelosuppression; latent tuberculosis or active chronic infections; confirmed pregnancy and active breastfeeding.
• Relative: Concomitant use with other hepatotoxic drugs such as methotrexate (synergistic risk of liver necrosis); mild interstitial lung disease.

Adverse Effects (ADR)

• Frequent / Tolerable: Nausea, dyspepsia, mild self-limited diarrhea, headache, transient hair loss (reversible alopecia), moderate weight loss, increase in systemic blood pressure (due to induced sympathetic stimulation of renal origin).
• Rare / Serious: Severe hepatotoxicity (intrahepatic cholestasis, fulminant hepatocyte necrosis); pancytopenia or aplastic anemia; acute interstitial pneumonitis; dermal hypersensitivity reactions (Stevens-Johnson syndrome); progressive distal peripheral neuropathy.

Drug Interactions

• Methotrexate: Synergistic immunomodulatory efficacy, but with an exponential increase in the rate of transaminasitis and risk of liver toxicity. Requires biweekly analytical monitoring.
• Warfarin: The active metabolite of leflunomide can competitively inhibit the CYP2C9 isoenzyme, reducing warfarin clearance and raising the INR with risk of bleeding.
• Cholestyramine or Active Charcoal: Drastically decreases serum levels of leflunomide due to interruption of enterohepatic recirculation.

Pregnancy and Breastfeeding

Classified in Category X of the FDA. It is an extremely potent human and animal teratogen that induces skeletal anomalies and hypoplasia of major fetal organs. Its initiation or maintenance in pregnant women or women who desire pregnancy is absolutely prohibited. If an accidental pregnancy is detected under treatment with leflunomide, the drug should be suspended and the accelerated elimination protocol with cholestyramine (8 g/3 times a day/11 days) should be started immediately until serum levels of A77 1726 below 0.02 mg/L are confirmed, measured in two determinations spaced at least 14 days apart. Breastfeeding: Contraindicated; The metabolites are excreted in milk, exposing the infant to neutropenia.