Pharmacokinetics and tolerance of mycophenolate mofetil in renal transplant children

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active i mmunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to ped iatric patients, although pharmacological data in this age group are limite d. Nine pediatric renal transplant recipients received MMF with corticoster oids and either cyclosporine or tacrolimus a median of 55 months (range 7.5 -124 months) months after transplantation. The pharmacokinetic parameters o f MPA and MPA glucuronide (MPAG) were determined at steady state by high-pe rformance liquid chromatography after administration of MMF at the oral dos e of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak c oncentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 mu g/ml. The areas under the plasma concentration-time curve s (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 mu g.h/ml for MPA and 1,515+/-722 mu g.h/ml for MPAG, and the apparent oral clearanc e was 11.7+/-7.0 and 0.5+/-0.4 1/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentratio n at steady state and the AUC for MPA were calculated for the recommended d osage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 mu g/ml and 75. 2+/-32.9 mu g.h/ml, respectively. The tolerance of MMF was studied prospect ively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requi ring dosage reduction or discontinuation of therapy, observed in five of ni ne patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated f rom adult data for use in pediatric patients would be associated with plasm a levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.