Leflunomide

Abstract

A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (≈2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily. Results of large randomised, double-blind, multicentre trials of up to 24 months’ duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians’ and patients’ global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patientsreceiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76 000 patients to date. Conclusions: Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months. Leflunomide is an immunomodulatory prodrug which is rapidly converted to its active metabolite, A77 1726, possibly in the gut wall, plasma and in the liver. A77 1726 inhibits cell proliferation in activated lymphocytes in patients with rheumatoid arthritis but its precise mechanism of action is unclear. In vitro data indicate that the drug inhibits dihydro-orotate dehydrogenase activity and protein tyrosine kinase activity in actively dividing cells. Additional pharmacodynamic effects of the drug, such as inhibition of nuclear factor κB activation and nuclear factor KB-dependent reporter gene expression and inhibitory effects on oxygen radical, immunoglobulin (Ig)G and IgM production and interleukin (IL)-Iβ and IL-2 levels, may also contribute to the immunomodulatory effects of A77 1726. Treatment with oral leflunomide 5 to 35 mg/kg/day decreased signs and symptoms of arthritis and histological evidence of joint damage in rodent models of rheumatoid arthritis and ankylosing spondylitis. The effects of leflunomide are at least additive with other disease-modifying antirheumatic drugs (DMARDS) such as cyclosporin and sirolimus (rapamycin) in vitro and in vivo. After oral administration, leflunomide is rapidly metabolised to its active metabolite, A77 1726, possibly in the gut wall, plasma and in the liver. Peak plasma A77 1726 concentrations are reached 6 to 12 hours after oral administration of leflunomide. In patients with rheumatoid arthritis, A77 1726 reaches steady-state plasma concentrations of 18 and 63 mg/L after administration of oral leflunomide 10 and 25 mg/day. A77 1726 is 99.38% bound to plasma proteins and has an apparent volume of distribution of 0.13 L/kg. The drug undergoes enterohepatic circulation and biliary recycling may contribute to its long elimination half-life (≈2 weeks). Because of the long elimination half-life, treatment with leflunomide should be initiated with a loading dose of 100mg once daily for 3 days to hasten attainment of steady-state plasma concentrations. 48% of the administered dose is excreted in the faeces and 43% in the urine. The drug was cleared at a rate of 0.031 L/h after intravenous administration and smokers tend to clear the drug at a faster rate than nonsmokers. Age and gender do not have any consistent effect on the pharmacokinetics of A77 1726. Plasma A77 1726 free fraction concentrations were higher in patients with rheumatoid arthritis and in patients chronic renal insufficiency than in healthy volunteers. A77 1726 is not dialysable. The effects of hepatic dysfunction on the pharmacokinetics of A77 1726 are unknown. Oral cholestyramine 8g 3 times a day for 24 hours or activated charcoal 50g every 6 hours for 24 hours are reported to rapidly decrease plasma A77 1726 concentrations (by 49 to 65% and 48%, respectively, after 48 hours). Coadministration of rifampicin (rifampin) increases peak plasma A77 1726 concentrations by ≈40%. No pharmacokinetic interactions have been reported after coadministration of leflunomide with triphasic oral contraceptives, methotrexate or cimetidine. Since A77 1726 inhibits cytochrome P450 (CYP) 2C9 in vitro, the...