Pharmacokinetics of mycophenolic acid (MPA) and free MPA in paediatric renal transplant recipients--a multicentre study. The German Study Group on Mycophenolate Mofetil (MMF) Therapy.

s 34 transplant, pharmacokinetic data for MPA in this time. This discrepancy can be attributed to a 35% decline (P<0.01) of the free MPA fraction from 1.4% patient population are scarce and dosage guidelines are therefore preliminary. (range 0.6–5.1%) in the initial phase post-transplant to 0.9% (range 0.5–1.9%) in the stable phase. The decrease of the free MPA fraction is probably caused Methods by several factors. First, the MPA-binding protein serum albumin increased into the normal range during We investigated the pharmacokinetics of MPA, free MPA the stable phase post-transplant in this study. Second, and the renal metabolite MPA glucuronide (MPAG) in the the improvement of kidney transplant function initial (sampling at 1 and 3 weeks) and stable phase (3 and during the study period, paralleled by a 40% decrease 6 months) post-transplant in 17 children (age 12.0±0.77 of the AUC 0–12 values of the renal metabolite MPAG, years; range 5.9–15.8 years) receiving the currently recommight have contributed to the decline of the free MPA mended dose of 600 mg MMF/m2 body surface area twice a fraction, because high MPAG plasma concentrations day. Blood samples were collected at 0, 20, 40 and 75 min and at 2, 4, 6, 8 and 12 h after dosing. Plasma concentrations have been shown to displace MPA from albuminof MPA and MPAG were measured by reverse-phase HPLC. binding sites. The mechanism of the increase of total Since MPA is bound extensively to serum albumin and only MPA-AUC 0–12 values in the stable phase postthe free drug is presumed to be pharmacologically active, we transplant is probably multifactorial and may involve also analysed the free MPA fraction by HPLC after separadecreased MPA metabolism as a consequence of the tion through ultrafiltration. Pharmacokinetic parameters 35% decline of the free MPA fraction, because it is were calculated with the biostatistical program BIASB. primarily the free drug that is available for metabolism. This hypothesis is supported by the observation of an Results inverse correlation (r=−0.61, P<0.02) between the decrease of the free MPA fraction and the increase of The intraindividual variability of the area under the the respective MPA-AUC 0–12 values in the stable vs concentration–time curves (AUC 0–12 ) of MPA initial phase post-transplant. throughout the 12 h dosing interval was high in the initial phase (correlation of 1 and 3 week AUC values: Conclusions r=0.17, P=0.51), but declined in the stable phase post-transplant (correlation of 3 and 6 month AUC Paediatric renal transplant recipients on a fixed MMF values: r=0.52, P<0.05), while the interindividual dose exhibit a 2-fold increase of the AUC 0–12 of total variability even increased in the stable phase (range MPA in the stable phase post-transplant and a 35% at 3 months, 81.4 mg×h/l; 6 months, 64.2 mg×h/l ) decrease of the free MPA fraction, whereas the compared with the initial phase (range at 1 week, AUC 0–12 of free MPA remains stable over time. 36.4 mg×h/l; 3 weeks, 43.1 mg×h/l ). The MPABecause the latter pharmacokinetic variable is theoretAUC 0–12 values increased 2-fold from 32.4 (range ically best predictive of the clinical immunosuppressive 13.9–57.0) mg×h/l at 3 weeks to 65.1 (range efficacy of MMF, these findings may have con32.6–114) mg×h/l at 3 months after grafting, whereas sequences for the dosing recommendations of MMF in renal transplant recipients. the AUC 0–12 values of free MPA did not change over Nephrol Dial Transplant (1999) 14 [Suppl 4]: 34–35 Therapeutic drug monitoring of total and free mycophenolic acid (MPA) and limited sampling strategy for determination of MPA-AUC in paediatric renal transplant recipients L. T. Weber1, E. Schütz3, T. Lamersdorf1, M. Shipkova3, P. D. Niedmann3, M. Oellerich3, L. B. Zimmerhackl2, A. Staskewitz2, O. Mehls1, V. W. Armstrong3, B. Tönshoff1 and the German Study Group on Mycophenolate Mofetil (MMF) Therapy 1University Children’s Hospitals Heidelberg and 2Freiburg and 3Department of Clinical Chemistry, Göttingen, Germany plant recipients. Currently, a fixed dose regimen Background (600 mg of MMF/m2 body surface area twice a day) Mycophenolate mofetil (MMF) is widely used for is recommended. However, in view of the considerable interindividual variability of mycophenolic acid (MPA) immunosuppressive therapy in paediatric renal transpharmacokinetics, it currently is being debated as to whether there is a need for a therapeutic drug monitoring of MPA to increase the clinical efficacy and Correspondence and offprint requests to: L. T. Weber, INF 150, 69120 Heidelberg, Germany. safety of its use by individualized MMF dosing. © 1999 European Renal Association–European Dialysis and Transplant Association