title: Customized mycophenolate dosing based on measuring inosine-monophosphate dehydrogenase activity significantly improves patients' outcomes after renal transplantation.
abstract: BACKGROUND
  Significant relationships have been reported between the uptake of mycophenolic acid (MPA) and the risk of acute rejection. In a prospective study after renal transplantation, we assessed the value of measuring inosine-monophosphate dehydrogenase (IMPDH) activity as a predictive indicator of an acute rejection episode in the initial postoperative period.
  
  
  METHODS
  Fifty-two patients received 360 mg enteric-coated mycophenolate-sodium two times per day with concomitant tacrolimus/cyclosporine A, providing a total of 122 pharmacodynamic profiles. IMPDH activity was measured by a validated high-performance liquid chromatography method in four plasma samples collected at predose, 30 and 60 min, 2 and 4 hr, and preoperative, during weeks 1 and 2 and 3 months after transplantation. MPA concentrations were measured by mass spectrometry. Inhibition of IMPDH was correlated to the MPA values, MPA area under the curves, and predose levels of the different calcineurin inhibitors.
  
  
  RESULTS
  Comparing the two groups (group I: rejection; n=17; mean age 51±15 years vs. group II: no rejection; n=35; mean age 51±14 years), we found a significantly (P<0.001) lower inhibition of IMPDH in group I (26.5%±11% vs. 56.7%±18%) already in the first week after transplantation. There was no correlation of MPA values (6.85±4 vs. 4.1±3 mg/L; first week) nor with the calcineurin inhibitor trough blood levels. Area under the curves for MPA did not differ significantly. Furthermore, IMPDH activity was a reliable predictor of rejection episodes and inflammation.
  
  
  CONCLUSIONS
  The data suggest that measuring biologic response may be a more valuable indicator than traditional therapeutic drug monitoring of MPA. Patients at risk for rejection could be earlier identified, and the therapeutic potential of MPA will be optimized.
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Raggi
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Siebert
authors.forename: Werner
authors.initials: W
authors.lastname: Steimer
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Manfred J
authors.initials: MJ
authors.lastname: Stangl
authors.forename: Dietmar K
authors.initials: DK
authors.lastname: Abendroth
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood* / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D007700:Kinetics; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D013607:Tablets; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D013607:Tablets; D016572:Cyclosporine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D016559:Tacrolimus