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 metabo lites, 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 t he plasma of transplant recipients. One of these metabolites (M-2), identif ied 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 releva nce of monitoring total (t-MPA) and free mycophenolic acid (f-MPA) in pedia tric renal transplant recipients. As in adults, a time-dependant increase o f t-MPA-AUC(0-12h) within the first 3 months posttransplant (35 versus 64 m g 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 ca ses with no complications and those with acute rejection, adverse events (s evere infections, leukopenia), or gastrointestinal disorders observed durin g 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 de termined by HPLC, seems to be a reasonable target for the early posttranspl ant period. It remains to be elucidated whether regular predose level monit oring may be of more practical value. A higher incidence of rejection was o bserved at predose MPA concentrations less than or equal to 1 mg/L, as meas ured by HPLC. In contrast to t-MPA, f-MPA-AUC(0-12h) was significantly rela ted 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 pharm acokinetics of MPA, the development of monitoring strategies for this drug appears to he promising.