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Articles |
Departments of
1
Kidney and Pancreas Transplantation and
2
Clinical Chemistry, University Hospital Saint Luc, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium.
aAddress correspondence to this author at: Department of Kidney and Pancreas Transplantation, University Hospital Saint Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium. Fax 32-2-770-7858; e-mail Michel.Mourad{at}chir.ucl.ac.be.
Background: Mycophenolate mofetil (MMF) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A (CsA) or tacrolimus (Tc). An increase in plasma mycophenolic acid (MPA) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc.
Methods: Adult kidney transplant recipients (n = 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids.
Results: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA cmin, 2.63 ± 1.58 vs 1.75 ± 0.82 mg/L (P = 0.016); mean c30, 10.47 ± 6.27 vs 7.66 ± 8.95 mg/L (P = 0.009); mean c60, 9.67 ± 5.42 vs 5.83 ± 2.6 mg/L (P = 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC(0–12)], 48.38 ± 18.5 vs 36.04 ± 10.82 mg · h/L (P = 0.0006); mean dose-normalized MPA-AUC, 0.16 ± 0.05 vs 0.12 ± 0.04 (mg · h/L)/(mg/m2) (P = 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA cmin values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC(0–12) values of 37.7, 24.9, and 104.9 mg · h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for cmin, 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg · h/L for MPA-AUC(0–12) (sensitivity, 83.3%; specificity, 59.6%).
Conclusions: These results demonstrate the relationship between plasma MPA concentrations and toxicity. High cmin, c30, and c60 values as well as AUC(0–12) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.
The following articles in journals at HighWire Press have cited this article:
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  I. Neumann, H. Fuhrmann, I-F. Fang, A. Jaeger, P. Bayer, and J. Kovarik Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil Nephrol. Dial. Transplant., June 27, 2008; (2008) gfn360v1. [Abstract] [Full Text] [PDF]
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W.-P. Yau, A. Vathsala, H.-X. Lou, and E. Chan Is a standard fixed dose of mycophenolate mofetil ideal for all patients? Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3638 - 3645. [Abstract] [Full Text] [PDF]
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 R. Borrows, G. Chusney, M. Loucaidou, A. James, S. Goel, S. Borrows, J. Van Tromp, T. Cairns, M. Griffith, N. Hakim, et al. Analysis of Factors Influencing Tacrolimus Levels and Immunoassay Bias in Renal Transplantation J. Clin. Pharmacol., August 1, 2007; 47(8): 1035 - 1042. [Full Text] [PDF]
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 H. Jeong and B. Kaplan Therapeutic Monitoring of Mycophenolate Mofetil Clin. J. Am. Soc. Nephrol., January 1, 2007; 2(1): 184 - 191. [Full Text] [PDF]
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 M Asfari, S Berta, S Coffy, M Kergoat, C Charon, and A Audet Short-term treatment with mycophenolic acid and tacrolimus is tolerogenic for INS-1 cell clone transplantation and the deleterious effects of the drugs are limited: in vivo and in vitro studies J. Endocrinol., July 1, 2005; 186(1): 213 - 220. [Abstract] [Full Text] [PDF]
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 B. Lumbreras-Lacarra, J. M. Ramos-Rincon, and I. Hernandez-Aguado Methodology in Diagnostic Laboratory Test Research in Clinical Chemistry and Clinical Chemistry and Laboratory Medicine Clin. Chem., March 1, 2004; 50(3): 530 - 536. [Abstract] [Full Text] [PDF]
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 I. Neumann, M. Haidinger, H. Jager, H. Grutzmacher, A. Griesmacher, M. M. Muller, P. M. Bayer, and F. Thomas Meisl Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared Renal Transplant Recipients J. Am. Soc. Nephrol., March 1, 2003; 14(3): 721 - 727. [Abstract] [Full Text] [PDF]
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L. T. Weber, M. Shipkova, V. W. Armstrong, N. Wagner, E. Schutz, O. Mehls, L. B. Zimmerhackl, M. Oellerich, and B. Tonshoff Comparison of the Emit Immunoassay with HPLC for Therapeutic Drug Monitoring of Mycophenolic Acid in Pediatric Renal-Transplant Recipients on Mycophenolate Mofetil Therapy Clin. Chem., March 1, 2002; 48(3): 517 - 525. [Abstract] [Full Text] [PDF]
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