Leflunomide

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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 drug may have potential for interaction with other drugs which are metabolised by this enzyme, such as diclofenac, ibuprofen and tolbutamide. Once daily oral leflunomide 20mg (after a loading dosage of 100mg once daily for 3 days) was effective in the treatment of adult patients with active rheumatoid arthritis in large randomised, double-blind, multicentre trials. Significant benefit with leflunomide was evident after 4 weeks’ and the drug had a faster onset of action than sulfasalazine or methotrexate. Improvement with leflunomide in all primary outcome measures, such as tender joint count, swollen joint count, physicians’ and patients’ global assessment of disease severity, and in American College of Rheumatology (ACR) 20 criteria were similar to those with sulfasalazine 2 g/day after 6 months. However, improvements from baseline in physicians’ and patients’ global assessment and ACR 20 responder rates were significantly better with leflunomide than with sulfasalazine after 24 months. The efficacy of leflunomide was broadly similar to that of methotrexate 7.5 to 15 mg/week. Improvement in all primary outcome measures with methotrexate was significantly better than with leflunomide after 12 months’ treatment in 1 trial, but there was no difference between the treatment groups in another trial of similar duration. Change from baseline in tender joint, patient’ global assessment and the ACR 20 responder rate were similar in leflunomide- or methotrexatetreated patients after 24 months. Furthermore, leflunomide was reported to be equivalent to methotrexate in an area-under-the-curve analysis of the ACR 20 responder rate. Leflunomide reduced functional disability to a significantly greater extent than sulfasalazine or methotrexate. Significantly greater benefit on functional disability with leflunomide than with sulfasalazine was evident after 6 months and was maintained over a period of up to 24 months. Leflunomide was significantly better than methotrexate in 5 of the 6 methods used to assess functional disability and quality of life in another trial of 12 months’ duration. Leflunomide is at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. Radiological progression of disease over 24 months was significantly slower with leflunomide or sulfasalazine than with placebo in 1 trial. Whereas radiological disease progression in leflunomide recipients was significantly less than that in patients receiving methotrexate or placebo in one 12-month trial, there was no difference in treatment-related delay in radiological disease progression after 12 and 24 months’ treatment with leflunomide or methotrexate in another trial. Preliminary data indicate that a combination of leflunomide with methotrexate is effective in patients with active rheumatoid arthritis refractory to methotrexate alone. However, the relative risks and benefits of using leflunomide with another DMARD have not been adequately evaluated. Leflunomide was as well tolerated as sulfasalazine or methotrexate in adult patients with active rheumatoid arthritis over durations of up to 24 months. The most common adverse effects (in ≥5% of recipients) with leflunomide were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic transferases (10%), dyspepsia (10%) and alopecia (9%), which were similar in intensity and severity to those with sulfasalazine or methotrexate. Of an estimated 76 000 patients who have received treatment with leflunomide, 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of the drug. The incidence and severity of increased serum hepatic enzymes with leflunomide (in up to 4.4% of recipients) were similar to those with sulfasalazine (3.8%) or methotrexate (2.7%). Although human data are lacking, animal data indicate that exposure to leflunomide during pregnancy has teratogenic and fetotoxic effects. The potential for male-mediated fetal toxicity with leflunomide has not yet been evaluated. However, male patients wishing to father a child should discontinue drug treatment should and hastened drug elimination procedure with cholestyramine or activated charcoal should be considered. Treatment with leflunomide should be initiated with a loading dose of 100mg administered once daily for 3 days and continued at a dosage of 20 mg/day. Dosages >20 mg/day are not recommended and the dosage may be decreased to 10 mg/day in those who cannot tolerate 20 mg/day. Serum hepatic enzymes should be monitored before initiating treatment with leflunomide and then at monthly intervals. The dosage of leflunomide does not have to be modified in patients >65 years of age, but the drug should be used with caution in patients with renal impairment. The use of leflunomide is contraindicated in female patients who are pregnant or are not using adequate contraception and in those who are breast-feeding infants. Treatment with leflunomide is not recommended in patients with significant hepatic impairment, positive hepatitis B or C serologies, severe immunodeficiency, bone marrow dysplasia or in those with severe uncontrolled infections.