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Keywords:

  • acyl glucuronide;
  • enteric-coated mycophenolate sodium;
  • immunosuppression;
  • IMPDH;
  • kidney transplantation;
  • mycophenolic acid

Stracke S, Shipkova M, Mayer J, Keller F, Zarghom A, Yang L, Henne-Bruns D, Wieland E. Pharmacokinetics and pharmacodynamics of mycophenolate sodium (EC-MPS) co-administered with cyclosporine in the early-phase post-kidney transplantation. Clin Transplant 2012: 26: 57–66. © 2011 John Wiley & Sons A/S.

Abstract:  Mycophenolate drug levels are decreased by co-administration of cyclosporine. However, mycophenolate levels may be associated with insufficient immunosuppression.

We investigated the pharmacokinetics of 720 mg mycophenolate sodium (EC-MPS) and inosine monophosphate dehydrogenase (IMPDH) activity under co-medication with cyclosporine and steroids within the first 30 d after kidney transplantation (n = 24). Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose. Plasma concentrations of mycophenolic acid, its glucuronide metabolites (MPAG; AcMPAG), and free MPA were determined using validated HPLC-DAD. IMPDH activity in leukocytes was analyzed chromatographically.

Only six of 24 patients had an MPA-AUC12h within the putative therapeutic range of 40–60 mg/L·h. MPA clearance was high with 29 L/h. fMPA-AUC12h (r = −0.429, p = 0.04) and MPAG-AUC12h correlated significantly with the glomerular filtration rate, while total MPA did not. The MPAG-AUC12h was about 52-fold higher than the corresponding values for MPA, whereas the AcMPAG-AUC12h reached about 20.4% of the respective MPA-AUC12h. We found significant correlations between IMPDH inhibition and MPA concentration (r = −0.665; p < 0.0001), fMPA (r = −0.446; p = 0.003), and AcMPAG (r = −0.459; p = 0.002) but not with MPAG.

Only 25% of the patients attained the therapeutic range for MPA-AUC under standard EC-MPS dose during the early-phase post-transplantation. We recommend that EC-MPS should be given in higher doses (3 × 720 mg) in the early post-transplant period when co-administered with cyclosporine.