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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.
a Author for correspondence. Fax 32-2-770-78-58;
Michel.Mourad{at}chir.ucl.ac.be
Background: Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation.
Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids.
Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA trough concentrations (Cmin) were 1.63 ± 1.07 and 2.29 ± 1.16 mg/L, respectively (P = 0.06), and the areas under the curve (AUCs) for MPA from t0 to t12 h (MPA-AUC0–12h) were 39.80 ± 15.29 and 62.10 ± 21.07 mg · h/L, respectively (P = 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-Cmin and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ± 0.45 mg/L and 25.00 ± 6.20 mg · h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [Cmin, the MPA concentration 30 min after the oral dose of MMF (C30), and AUC] according to the presence or absence of side effects in the two groups. Cmin and AUC did not differ between the two groups [Cmin = 2.22 ± 1.13 vs 2.17 ± 1.13 mg/L (P = 0.9); AUC = 66.82 ± 29.87 vs 55.70 ± 11.74 mg · h/L (P = 0.11)]; and C30 was significantly higher in group 2 than in group 1 (C30 = 32.99 ± 12.59 vs 7.45 ± 5.40 mg/L; P <0.0001).
Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.
The following articles in journals at HighWire Press have cited this article:
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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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 L. M. Shaw, M. Figurski, M. C. Milone, J. Trofe, and R. D. Bloom Therapeutic Drug Monitoring of Mycophenolic Acid Clin. J. Am. Soc. Nephrol., September 1, 2007; 2(5): 1062 - 1072. [Full Text] [PDF]
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 L. Giaccone, J. S. McCune, M. B. Maris, T. A. Gooley, B. M. Sandmaier, J. T. Slattery, S. Cole, R. A. Nash, R. F. Storb, and G. E. Georges Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation Blood, December 15, 2005; 106(13): 4381 - 4388. [Abstract] [Full Text] [PDF]
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 G. R. Ingle and T. Shah Enteric-coated mycophenolate sodium for transplant immunosuppression Am. J. Health Syst. Pharm., November 1, 2005; 62(21): 2252 - 2259. [Abstract] [Full Text] [PDF]
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 K. K. Miles, S. T. Stern, P. C. Smith, F. K. Kessler, S. Ali, and J. K. Ritter AN INVESTIGATION OF HUMAN AND RAT LIVER MICROSOMAL MYCOPHENOLIC ACID GLUCURONIDATION: EVIDENCE FOR A PRINCIPAL ROLE OF UGT1A ENZYMES AND SPECIES DIFFERENCES IN UGT1A SPECIFICITY Drug Metab. Dispos., October 1, 2005; 33(10): 1513 - 1520. [Abstract] [Full Text] [PDF]
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 R. G Morris Immunosuppressant Drug Monitoring: Is the Laboratory Meeting Clinical Expectations? Ann. Pharmacother., January 1, 2005; 39(1): 119 - 127. [Abstract] [Full Text] [PDF]
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 T. M. Sievers New Antiproliferative Immunosuppressive Agents Journal of Pharmacy Practice, December 1, 2003; 16(6): 401 - 413. [Abstract] [PDF]
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M. H. Ensom, N. Partovi, D. Decarie, A. P Ignaszewski, G. J Fradet, and R. D Levy Mycophenolate Pharmacokinetics in Early Period Following Lung or Heart Transplantation Ann. Pharmacother., December 1, 2003; 37(12): 1761 - 1767. [Abstract] [Full Text] [PDF]
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 G. A. Knoll, I. MacDonald, A. Khan, and C. van Walraven Mycophenolate Mofetil Dose Reduction and the Risk of Acute Rejection after Renal Transplantation J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2381 - 2386. [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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 T. Pawinski, M. Hale, M. Korecka, W. E. Fitzsimmons, and L. M. Shaw Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area under the Curve in Adult Renal Transplant Patients Treated with Concomitant Tacrolimus Clin. Chem., September 1, 2002; 48(9): 1497 - 1504. [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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M. Mourad, J. Malaise, D. Chaib Eddour, M. De Meyer, J. Konig, R. Schepers, J. P. Squifflet, and P. Wallemacq Pharmacokinetic Basis for the Efficient and Safe Use of Low-Dose Mycophenolate Mofetil in Combination with Tacrolimus in Kidney Transplantation Clin. Chem., July 1, 2001; 47(7): 1241 - 1248. [Abstract] [Full Text] [PDF]
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