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. PATIENTS AND 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. CONCLUSION: 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.