EXPERIENCES WITH LEFLUNOMIDE IN SOLID ORGAN TRANSPLANTATION

Publisher Website
Google Scholar
Abstract
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 μg/mL (300 μM) 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 often required serum levels of active drug reduced to Conclusion. 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 μg/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.