Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression

The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m(2) twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophe nolic acid (MPA) pre-dose trough concentration between 2 and 5 mu g/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m(2) b.i.d.. I n order to investigate whether this striking difference was due to alterati ons of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patie nts who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who re ceived MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9+/-23.8 mu gxh/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving co ncomitant FK506 compared with CyA, and the dose-normalized AUC was signific antly higher. The MMF doses were 1,158+/-301 mg/m(2) per day in the CyA gro up, 555+/-289 mg/m(2) per day in the tacrolimus group, and 866+/-401 mg/m(2 ) per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. T he reason for this remains unknown. There was a trend towards lower dose-no rmalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the cle arance of MPA, It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and th erefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m(2) b.i.d,, in combination with tacrolimus at a dose of 300 mg/m(2) b.i .d,, and without a calcineurin inhibitor at a dose of 500 mg/m(2) b.i.d., a nd adjusting doses using therapeutic drug monitoring of MPA.