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. 2005 Sep;60(3):249-56.
doi: 10.1111/j.1365-2125.2005.02398.x.

Characterizing the role of enterohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling

Serge Cremers  1 , Rik Schoemaker, Eduard Scholten, Jan den Hartigh, Jacqueline König-Quartel, Eric van Kan, Leendert Paul, Johan de Fijter
Affiliations

Characterizing the role of enterohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling

Serge Cremers et al. Br J Clin Pharmacol. 2005 Sep.

Abstract

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.

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Figures

Figure 1
Figure 1
Four-compartment model for the pharmacokinetics of mycophenolate mofetil (MMF); MPA = mycophenolic acid, MPAG = mycophenolate glucuronide, tabs = absorption half-life, q = intercompartmental clearance, Cl = clearance of MPA into MPAG, k40 = elimination rate constant of MPAG, k41 = rate transfer constant describing biliary excretion of MPAG
Figure 2
Figure 2
Average (±SD) graph of observed data (black markers: CsA, white markers: TACR) with average predicted curves from weeks 12, 26 and 52 combined; top graph: MPA, bottom graph: MPAG
Figure 3
Figure 3
Average (±SD) empirical Bayes estimates of clearance of MPA, clearance of MPAG and k40 during 1 year post transplantation calculated using the four-compartment model without (left side of the figure) and with the use of k41 in case of TACR co-administration (right side of the figure); white markers represent TACR and black markers CsA comedication
See this image and copyright information in PMC

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