Clinical Pharmacokinetic Monitoring of Leflunomide in Renal Transplant Recipients with BK Virus Reactivation: A Review of the Literature

Abstract

Leflunomide is an immunosuppressive drug with in vitro and initial observational evidence of antiviral activity against BK virus (BKV), a pathogen that causes opportunistic infection upon reactivation in renal transplant recipients. Leflunomide is considered an ancillary option to immunosuppression reduction in the management of BKV reactivation. Plasma or blood concentrations of teriflunomide, the active metabolite of leflunomide, are commonly monitored because of high leflunomide doses being used, known inter-individual variability in pharmacokinetics, and hepatotoxicity risk. However, the utility of clinical pharmacokinetic monitoring for leflunomide is as yet unclear. A literature search of MEDLINE (1946-December 2016), EMBASE (1974-December 2016), the CENTRAL database, and Google Scholar was performed to identify relevant English-language articles. Further articles were identified from references in relevant literature. A previously published 9-step decision-making algorithm was used to assess the available literature and determine the utility of clinical pharmacokinetic monitoring for leflunomide. Teriflunomide is readily measurable in the plasma or blood, but a clear relationship between concentration and efficacy or toxicity is lacking, and its therapeutic range is not well-established. Efficacy and toxicity endpoints such as renal function and BKV clearance can be readily assessed without measuring teriflunomide concentrations. Pharmacokinetic parameters are affected by genetic polymorphisms in cytochrome P450 CYP2C19 and ABCG2 genes. Therefore, routine clinical pharmacokinetic monitoring of leflunomide cannot be recommended based on current available evidence. However, it may provide clinical benefit in difficult situations when patients demonstrate a lack of therapeutic response or exhibit signs of drug toxicity.

Keywords: Cidofovir; Enterohepatic Recirculation; Leflunomide; Renal Transplant Recipient; Teriflunomide.