The Impact of Renal Allograft Function on Exposure and Elimination of Mycophenolic Acid (MPA) and Its Metabolite MPA 7-O-glucuronide

Abstract

Previous studies have shown that total-body clearance of mycophenolic acid (MPA) is increased and total MPA exposure decreased in renal allograft recipients with severe renal dysfunction. In contrast to these studies, other studies have associated renal impairment with higher MPA exposure. The reason for these inconsistencies is not clear. In 120 renal allograft recipients with stable graft function and treated with a combination of mycophenolate mofetil, tacrolimus, and corticosteroids, clinical determinants of exposure to total MPA and its glucuronide metabolite MPA 7-O-glucuronide (MPAG) were investigated in a multivariate regression model at 3 (n=118) and 12 (n=63) months after transplantation. Almost 50% of total MPA exposure could be explained by the final model, in which proteinuria, glomerular filtration rate, diabetes mellitus, and the mycophenolate mofetil dose were independent determinants of total MPA exposure. Lower glomerular filtration rate (GFR) was independently associated with higher MPA exposure both at 3 and 12 months after transplantation. GFR, alanine aminotransferase, and serum albumin levels and mycophenolate mofetil dose explained 69% of total MPAG exposure variability. In stable renal recipients, total MPA exposure negatively associates with renal function, through accumulation of both MPA and MPAG in patients with moderately reduced renal allograft function. This is in contrast to severe graft dysfunction, where MPA clearance is higher due to increased free fraction of MPA, as shown in previous studies. The duality in the effect of graft function on MPA pharmacokinetics is of clinical importance, adjusting mycophenolate mofetil dose according to renal function might help to avoid side effects and improve efficacy.