Experiences with leflunomide in solid organ transplantation

Leflunomide (Arava), a drug widely used for treatment of rheumatoid arthritis, has a very promising background in experimental transplantation. Its activity in experimental models of chronic rejection, its synergy with calcineurin phosphatase inhibitors, and its inhibitory effects on herpes virus replication are compelling reasons to pursue its clinical evaluation in transplantation. We report the use of this drug over the past 3 years in various clinical situations.

A retrospective review was performed in 53 liver and kidney transplant recipients receiving Arava. A single-dose pharmacokinetic (PK) study was first performed in stable, renal transplant recipients, and an initially targeted serum level of 100 microg/mL (300 microM) was calculated to require a loading dose of 1200-1400 mg over a 7-day period. We correlate the appearance of toxicity with serum levels of active drug and review the outcomes in patients whose clinical condition required dose reductions of conventional immune suppressive drugs.

Fifty-three patients received leflunomide from 5 days to more than 430 days, and 37 patients received the drug for more than 60 days. The primary toxicity was anemia in the renal transplant patients and elevation of liver enzymes in the liver transplant patients. At comparable oral doses, serum levels were substantially lower and anemia more common in patients with serum creatinine >3 mg/dL. In liver and renal recipients with serum creatinine <3 mg/dL, the drug was well tolerated and dose-limiting side effects occurred in less than 15% when drug serum levels were less than 80 microg/ml. Patients with serum creatinine >3 mg/dL often required serum levels of active drug reduced to <60 microg/mL. In 12 of 18 renal patients treated for 200 days or more, the dose of cyclosporine or Prograf was reduced by a mean of 38.5% and stopped in one patient. The prednisone dose was reduced by a mean of 25% in these same 13 patients. Cyclosporine or FK506 was stopped completely in four liver recipients and reduced by 65% in another patient. No evidence of acute rejection developed in any of these liver or kidney transplant patients.

Leflunomide seems to possess substantial immune suppressive potency in renal and liver transplant recipients and may be safely dosed for more than 300 days. The data suggest that calcineurin phosphatase inhibitors and prednisone can be safely reduced in patients with serum levels of active drug above 50 microg/mL. Because of a wide inter-patient range of active metabolite terminal half-life (>300%), monitoring of serum levels would seem to be an important part of its evaluation.