Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation:: Implications for therapeutic drug monitoring

The need for mycophenolic acid (MPA) monitoring is still under discussion. Key issues for the PK/PD relationships of this drug are: the role of metabolites, the usefulness of AUC versus predose levels, and the need to monitor the free concentration of MPA (f-MPA). Recent advances have revealed that, in addition to 7-O-MPAG, three additional MPA metabolites are present in the plasma of transplant recipients. One of these metabolites (M-2), identified as an acyl glucuronide of MPA, was found to inhibit IMPDH-II in vitro. This active metabolite was also found to cross-react in the Emit assay for MPA. In an ongoing multicenter study, the authors are evaluating the relevance of monitoring total (t-MPA) and free mycophenolic acid (f-MPA) in pediatric renal transplant recipients. As in adults, a time-dependant increase of t-MPA-AUC(0-12h) within the first 3 months posttransplant (35 versus 64 mg x L/h, 3 weeks versus 3 months respectively; daily dosage: 0.6 g/m(2) bid) was seen. Receiver operating characteristics curve analyses were used to test the ability of predose levels or AUC(0-12h) to discriminate between cases with no complications and those with acute rejection, adverse events (severe infections, leukopenia), or gastrointestinal disorders observed during the early posttransplant course, In agreement with observations in adults, a significant (p = 0.001) association was observed between AUC(0-12h) and acute rejection. A t-MPA-AUC(0-12h) of approximately 30-60 mg x L/h, as determined by HPLC, seems to be a reasonable target for the early posttransplant period. It remains to be elucidated whether regular predose level monitoring may be of more practical value. A higher incidence of rejection was observed at predose MPA concentrations less than or equal to 1 mg/L, as measured by HPLC. In contrast to t-MPA, f-MPA-AUC(0-12h) was significantly related to seven infections and leukopenia. The risk for severe adverse events was increased at f-MPA- AUC(0-12h) values greater than or equal to 600 mu g x Uh. On the basis of these data and the observed variability in the pharmacokinetics of MPA, the development of monitoring strategies for this drug appears to he promising.