Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: A longitudinal study in pediatric patients

Mycophenolate mofetil, an ester prodrug of the immunosuppressant mycophenol ic acid (MPA), is widely used for maintenance immunosuppressive therapy in pediatric renal transplant recipients. However, little is known about the p harmacokinetics of MPA in this patient population in the stable transplant phase, and dosage: guidelines are preliminary. The authors therefore compar ed the pharmacokinetics of MPA, free MPA, and the renal metabolite MPA gluc uronide (MPAG) in the initial (sampling at 1 and 3 weeks) and stable phases (sampling at 3 and 6 months) post-transplant in 17 children (age, 12.0 +/- 0.77 years; range, 5.9 to 15.8 years), receiving the currently recommended dose of 600 mg MMF/m(2) body surface area (BSA) twice a day. Plasma concen trations of MPA and MPAG were measured by reverse phase HPLC. Because MPA i s extensively bound to serum albumin and only the free drug is presumed to be pharmacologically active, the authors also analyzed the MPA fi ee fracti on by HPLC after separation by ultrafiltration. The intraindividual variabi lity of the area under the concentration-time curves (AUC(0-12)) of MPA thr oughout the 12-hour dosing interval was high in the immediate posttransplan t period, but declined in the stable phase, whereas the interindividual var iability remained unchanged. The median MPA-AUC(0-12) values increased 2-fo ld from 32.4 (range, 13.9 to 57.0) mg x h/L at 3 weeks to 65.1 (range, 32.6 to 114) mg x h/L at 3 months after transplantation, whereas the median AUC (0-12) values of free MPA did not significantly change over time. This disc repancy can be attributed to a 35% decline of the MPA free fraction from 1. 4% in the initial phase posttransplant to 0.9% (p < 0.01) in the stable pha se. In conclusion, pediatric renal transplant recipients given a fixed MMF dose exhibit a 2-fold increase of the AUC(0-12) of total MPA in the stable phase posttransplant and a 35% decrease of the MPA free fraction, whereas t he AUC(0-12) of free MPA remains unchanged over time. Because the latter ph armacokinetic variable is theoretically best predictive of the clinical imm unosuppressive efficacy of MMF, these findings may have consequences for th e dosing recommendations of MMF in renal transplant recipients.