Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatric and adult renal transplant recipients. German Study group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients.

Dosage guidelines for mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophe- nolic acid (MPA), are still preliminary in children. This study compares the pharmacokinetics of MPA and its major metab- olite MPA glucuronide (MPAG) in pediatric renal transplant recipients receiving 600 mg MMF/m2 body surface area twice a day to those of adults on the currently recommended oral dose of I g of MMF twice a day. Concentration-time profiles of 18 children (age, 10.7 ± 0.72 yr; range, 5.9 to 15.3 yr) and 10 adults were investigated 1 and 3 wk after transplantation. Plasma concentrations of MPA and MPAG were measured by reverse-phase HPLC. Because MPA is extensively bound to serum albumin and only the free fraction is presumed to be pharmacologically active, the MPA free fraction was also analyzed by HPLC after separation through ultrafiltration. The areas under the concentration-time curves (AUC0_12) of total and free MPA throughout the 12-h dosing interval in children were, in general, comparable to the corresponding data in adult patients. The mean AUCQ_12 of MPA and free MPA did not change significantly over the first 3 wk after transplantation, but there was substantial intra- and interindividuab variation. MPAG-AUC0_12 values in children with primary renal trans- plant dysfunction were threefold higher than in those with functioning transplants. Renal impairment had no consistent effect on total MPA-AUC0_12 values, but the MPA free frac- tion in children (median, 1.65%; range, 0.40 to 13.8%) was significantly (,.2 0.46) modulated by renal transplant fune- tion and serum albumin levels. In conclusion, concentration- time profiles of pediatric renal transplant recipients adminis- tered 600 mg MMF/m2 body surface area twice a day are comparable to those in adults on I g MMF twice a day in the first 3 wk after transplantation. Renal impairment and de- creased serum albumin levels led to an increase in the free fraction of MPA and the free MPA-AUC�12 values. Because the pharmacologic activity of MPA is a function of unbound drug concentration, these findings might be relevant for the pharmacodynamie effects of MPA. Mycophenolate mofetil (MMF), an ester prodrug of the immuno- suppressant mycophenolic acid (MPA), has recently been ap- proved both in adults and children for maintenance immunosup- pressive therapy after renal transplantation. MPA is a potent, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase, and thus MPA acts as a relatively selective inhib- itor of T and B cell proliferation by blocking the production of