Characterizing the Role of Enterohepatic Recycling in the Interactions Between Mycophenolate Mofetil and Calcineurin Inhibitors in Renal Transplant Patients by Pharmacokinetic Modelling

Background: Controversy remains about the interaction between mycophenolate mofetil (MMF) and the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (TACR). The need to double the dose of MMF in case of CsA co-administration to achieve the same mycophenolic acid (MPA) levels as in TACR co-administration, has been attributed to either inhibition by CsA of the enterohepatic cycle, or an inhibition of glucuronidation to mycophenolate glucuronide (MPAG) by TACR. We explored these interactions clinically in 64 kidney transplant patients.

Methods: Plasma MPA/MPAG curves were determined during the first year post transplantation. Using nonlinear mixed effect modelling, MPA/MPAG data were fitted to a four-compartment model, in which a rate constant describing transfer from the fourth to the first compartment (k41), and therefore enterohepatic recycling, could be introduced.

Results: MPA and MPAG plasma concentrations were adequately described by a four-compartment model, which was significantly improved by introduction of k41 in case of TACR co-administration (minimum value of the objective function decreased by 181 points, P < 0.0001). Using this model, no statistically significant difference was observed in clearance of MPA between TACR and CsA co-administration (11.9 and 14.1 l h(-1), respectively). Total clearance of MPAG was lower in case of CsA co-administration (1.45 and 0.92 l h(-1), respectively), while there was no difference in renal clearance of MPAG (1.09 and 0.92 l h(-1), respectively).

Conclusions: Our study supplies supportive clinical evidence that inhibition of the enterohepatic cycle in case of CsA co-administration explains some of the differences observed in PK of MMF when co-administered with either TACR or CsA. This finding may have clinical consequences for the immunosuppressive management of kidney transplant patients.