Lefno Mechanism of Action

Pharmacotherapeutic group: Selective immunosuppressants. ATC code: L04AA13.
Pharmacology: Pharmacodynamics: Human pharmacology: Leflunomide is a disease-modifying anti-rheumatic agent with antiproliferative properties. Leflunomide has shown to improve signs and symptoms and to slow down the progression of joint destruction in active rheumatoid arthritis. In the respective studies the large majority of patients used concomitant NSAIDs or low doses of corticosteroids.
Animal pharmacology: Leflunomide is effective in animal models of arthritis and of other autoimmune diseases and transplantation. It has immunomodulating/immunosuppressive characteristics, acts as an antiproliferative agent, and displays anti-inflammatory properties.
In vivo, it is rapidly and almost completely metabolized to A771726 which is active in vitro, and is presumed to be the active medicinal product.
Leflunomide exhibits the best protective effects on animal models of autoimmune diseases when administered in the early phase of the disease progression. In animal models of chronic graft versus host disease and solid organ graft rejection, leflunomide has prolonged rejection time or reversed ongoing rejection reactions. In addition, leflunomide has exhibited anti-inflammatory activity, yet only weak to no analgesics or antipyretic activity. In a model of experimental septicaemia, leflunomide did not alter the resistance of mice to bacterial pathogens.
Mechanism of action: A771726, the active metabolite of leflunomide, slows down the progress of target cells through different phases of cell cycle. In vitro, alter mitogen stimulation, A771726, the active metabolite, inhibits T-cell proliferation and DNA synthesis. It inhibits mitogen-stimulated proliferation of human peripheral blood mononuclear cells (PBMCs), and proliferation in transformed murine and human cell lines, in a dose-dependent fashion. This antiproliferative activity is reversed by the addition of uridine to the cell culture, indicating that A771726 acts at the level of the pyrimidine biosynthesis pathway. Binding studies using radiolabeled ligand demonstrate that the active metabolite binds to and inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Together, these data suggest that, in vivo, at concentrations achievable in patients receiving leflunomide, pyrimidine synthesis in lymphocytes and other rapidly dividing cell populations may be inhibited. Further, the inhibition of tyrosine kinase activity has been reported, for both in vitro and in vivo situations. The in vitro activity does not seem to be mediated directly through enzyme inhibition and takes place only at much higher concentrations of A771726 than is necessary for the inhibition of DHODH.
Pharmacokinetics: Leflunomide is rapidly converted to the active metabolite, A771726, by first-pass metabolism (ring opening) in gut wall and liver. In a study with radiolabeled ¹⁴C-leflunomide in three healthy volunteers, no unchanged leflunomide was detected in plasma, urine or feces. In other studies, unchanged leflunomide levels in plasma have rarely been detected, however, at ng/ml plasma levels. The only plasma radiolabeled metabolite detected was A771726. This metabolite is responsible for essentially all the in vivo activity of Leflunomide.
Absorption: Excretion data from the ¹⁴C study indicated that at least about 82 to 95% of the dose is absorbed. The time to peak plasma concentrations of A771726 is very variable; peak plasma levels can occur between 1 hour and 24 hours after single administration. Leflunomide can be administered with food, since the extent of absorption is comparable in the fed and fasting state. Due to the very long half-life of A771726 (approximately 2 weeks), a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state levels of A771726. Without a loading dose, it is estimated that attainment of steady-state plasma concentrations would require nearly two months of dosing. In multiple dose studies in patients with rheumatoid arthritis, the pharmacokinetic parameters of A771726 were linear over the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and to the daily dose of leflunomide. At a dose level of 20 mg/day, average plasma concentration of A771726 at steady state is approximately 35 μg/ml. At steady state plasma levels accumulate about 33- to 35-fold compared with single dose.
Distribution: In human plasma, A771726 is extensively bound to protein (albumin). The unbound fraction of A771726 is about 0.62%. Binding of A771726 is linear in the therapeutic concentration range. Binding of A771726 appeared slightly reduced and more variable in plasma from patients with rheumatoid arthritis or chronic renal insufficiency. The extensive protein binding of A771726 could lead to displacement of other highly-bound drugs. In vitro plasma protein binding interaction studies with warfarin at clinically relevant concentrations, however, showed no interaction. Similar studies showed that ibuprofen and diclofenac did not displace A771726, whereas the unbound fraction of A771726 is increased 2- to 3-fold in the presence of tolbutamide. A771726 displaced ibuprofen, diclofenac and tolbutamide but the unbound fraction of these drugs is only increased by 10% to 50%. There is no indication that these effects are of clinical relevance. Consistent with extensive protein binding A771726 has a low apparent volume of distribution (approximately 11 liters). There is no preferential uptake in erythrocytes.
Metabolism: Leflunomide is metabolized to one primary (A771726) and many minor metabolites including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions. Interaction studies with cimetidine (non-specific cytochrome P450 inhibitor) and rifampicin (non-specific cytochrome P450 inducer), indicate that in vivo CYP enzymes are involved in the metabolism of leflunomide only to a small extent.
Elimination: Elimination of A771726 is slow and characterized by an apparent clearance of about 31 ml/hr. The elimination half-life in patients is approximately 2 weeks. After administration of a radiolabelled dose of leflunomide, radioactivity was equally excreted in faeces, probably by biliary elimination, and in urine. A771726 was still detectable in urine and faeces 36 days after a single administration. The principal urinary metabolites were glucuronide products derived from leflunomide (mainly in 0 to 24 hours samples) and an oxanilic acid derivative of A771726. The principal faecal component was A771726.
It has been shown in man that administration of an oral suspension of activated powdered charcoal or colestyramine leads to a rapid and significant increase in A771726 elimination rate and decline in plasma concentrations (see Overdosage). This is thought to be achieved by a gastrointestinal dialysis mechanism and/or by interrupting enterohepatic recycling.
Pharmacokinetics in renal failure: Leflunomide was administered as a single oral 100 mg dose to 3 hemodialysis patients and 3 patients on continuous peritoneal dialysis (CAPD). The pharmacokinetics of A771726 in CAPD subjects appeared to be similar to healthy volunteers. A more rapid elimination of A771726 was observed in hemodialysis subjects which was not due to extraction of drug in the dialysate but instead to displacement of protein binding. Population kinetic analysis of all 6 of these patients demonstrated that although clearance of A771726 is increased approximately 2-fold, terminal half-life of elimination is similar to that for healthy subjects since the volume of distribution is also increased.
Pharmacokinetics in liver failure: No data are available regarding treatment of patients with hepatic impairment. The active metabolite A771726 is extensively protein bound and cleared via hepatic metabolism and biliary secretion. These processes may be affected by hepatic dysfunction.
Pharmacokinetics in Pediatrics: The pharmacokinetics of A771726 following oral administration of leflunomide have been investigated in 73 pediatric patients with polyarticular course Juvenile Rheumatoid Arthritis (JRA) who ranged in age from 3 to 17 years. The results of a population pharmacokinetic analysis of these trials have demonstrated that pediatric patients with body weights ≤40 kg have a reduced systemic exposure (measured by C_ss) of A771726 relative to adult rheumatoid arthritis patients (see Dosage & Administration).
Influence of age: Pharmacokinetics in children and adolescents have not been studied. Pharmacokinetic data in elderly (>65 years) are limited but consistent with pharmacokinetics in younger adults.
Smoking: A population-based pharmacokinetic analysis of the Phase III data indicated that smokers had a 38% increase in clearance over nonsmokers; however, no difference in clinical efficacy was seen between smokers and nonsmokers.