Pharmacokinetic basis for the efficient and safe use of low-dose mycophenolate mofetil in combination with tacrolimus in kidney transplantation

Background: Mycophenolate mofetil (MMF) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A (CsA) or ta crolimus (Tc). An increase in plasma mycophenolic acid (MPA) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF com bination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/ pharmacodynamic (PK/PD) relationship fo r MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. Methods: Adult kidney transplant recipients (n = 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dos e) were obtained within the first 2 weeks after transplantation, 3 months a fter grafting, and at every adverse clinical event [side effect or acute re jection (AR)]. All patients received Tc, MMF (500 mg twice a day), and ster oids. Results: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total o f 78 MPA-PK profiles were obtained. The following PK parameters were increa sed in the side-effects group compared with the non-side effects group: mea n MPA c(min), 2.63 +/- 1.58 vs 1.75 +/- 0.82 mg/L (P = 0.016); mean c(30), 10.47 +/- 6.27 vs 7.66 +/- 8.95 mg/L (P = 0.009); mean c(60), 9.67 +/- 5.42 vs 5.83 +/- 2.6 mg/L (P = 0.0002); mean area under MPA time-concentration curve from 0 to 12 h [MPA-AUC((0-12))], 48.38 +/- 18.5 vs 36.04 +/- 10.82 m g h/L (P = 0.0006); mean dose-normalized MPA-AUC, 0.16 +/- 0.05 vs 0.12 +/- 0.04 (mg(.)h/L)/(mg/m(2)) (P = 0.0015). For the three AR patients, MPA con centrations obtained at the time of AR revealed MPA c(min) values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC((0-12)) values of 37.7, 24.9 , and 104.9 mg h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7 %; specificity, 91.5%) for c(min), 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg h/L for MPA-AUC((0-12)) (sensitivity, 83.3%; specificity, 59.6%). Conclusi ons: These results demonstrate the relationship between plasma MPA concentr ations and toxicity. High c(min), c(30), and c(60) values as well as AUC((0 -12)) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program. (C) 2001 American Asso ciation for Clinical Chemistry.