Limits to Intensified Dosing of Mycophenolate Mofetil in Kidney Transplantation

Abstract

Introduction: Several studies have shown that achieving adequate exposure of mycophenolic acid (MPA) early post transplant is associated with less acute rejection in kidney recipients. Intensified dosing with the equivalent of mycophenolate mofetil (MMF) 3 g daily in tacrolimus treated patients has been shown to increase exposure. However about 15% of patients remain below the lower therapeutic threshold as determined by an MPA aea under the curve (AUC) of 30 mg*hr/L early post transplant (CLEAR Study CJASN 2010). Our earlier analysis of this study also showed that a target MPA AUC >45 mg*hr/L was most effective. Methods: In this study MMF 4 g taken orally (2 g twice daily) was used in tacrolimus treated de novo kidney transplant recipients (single arm) to see if all patients would exceed the MPA AUC threshold of 30 mg*hr/L early post transplant. MPA AUCs were done on day 5 and 14. Doses were adjusted if exposure on day 5 was high. A 3-point limited sample strategy was used to measure MPA AUC. Results: In 30 patients the mean AUC was 63±28 on day 5, with 13% (4/30) ≤ 30 mg*hr/L and 57% (17/30) >60 mg*hr/L. Only 30% (9/30) were in the window between 30 and 60 mg*hr/L. The target AUC of 45 mg*hr/L was not reached in 26% (8/30). Three patients developed gastrointestinal toxicity, required dose changes and were not related to MPA levels. To date acute rejection occurred in only 2 patients (Grade IA and IIB) within 3 months (day 5 MPA AUCs were 29.9 and 33 mg*hr/L). On day 14 the the mean MPA AUC was 46±8 mg*hr/L, with13% still below the 30 mg*hr/L threshold but 50% were now within the 30-60 mg*hr/L window. On day 14, 60% of the patients were on MMF doses >2 g daily (9 on 3 g and 9 on 4 g daily). Conclusion: Compared to MMF 3 g daily in the CLEAR study, 4 g daily did not reduce the number of patients whose MPA concentrations fell below the recommended MPA AUC threshold by day 5. Rejections were few in this study and occurred in the lower MPA exposed recipients. More than 50% of tacrolimus treated patients will need doses of MMF >2 g daily for 2 weeks to avoid underexposure and most will tolerate the increased dose. Intensified dosing with limited monitoring may improve outcomes compared to standard 2 g daily, but 10-15% will remain underexposed despite the higher initial dose.