ESTIMATION OF MYCOPHENOLATE ACID AREA UNDER THE CURVE THROUGH A LIMITED SAMPLING STRATEGY IN RENAL TRANSPLANT RECIPIENTS TREATED WITH CONCOMITANT SIROLIMUS

A237 Introduction: Efficacy and side effects of mycophenolate mofetil (MMF) are better correlated to area under the curve (AUC0-12) than to trough concentrations. Contrarily to cyclosporine A (CsA), tacrolimus (Tacro) has been shown not to interact with mycophenolate acid (MPA) pharmacokinetics. Limited sampling strategies (LSS) have been developed for MPA AUC0-12 estimation in patients treated either with CsA or with Tacro. Very few is known about MPA0-12 pharmacokinetics when associated with the new immunosuppressive drug Sirolimus (Sir). Aims: We hypothesized that the LLS developed for MPA AUC estimation in patients treated with Tacro might be applied in patients receiving Sir. We therefore investigated the PK profile of MPA0-12 in renal graft recipients treated with concomitant Sir. Methods: Eighteen renal graft recipients were treated with ATG (Thymoglobuline®) from day 1 to day 5 post-transplant together with Sir (Rapamune®) at 15, 10 and 10 mg/d respectively from day 1 to day 3 and then dose was adapted to obtain a trough concentration of 10-20 ng/ml, MMF (Cellcept®) at a fixed dose of 2 g/d and steroids at 1 mg/kg/d and tapered to 10 mg/d at 3 months. Pharmacokinetic analysis of blood MPA concentrations were performed on day 15, and 1, 2 and 3 months after transplantation. For each patient a total of 10 blood samples were collected at predose, and 20 min, 30 min, 1h, 1h30, 2h, 3h, 4, 6h and 9h after MMF intake. Reference AUCs over 12h were estimated using the trapezoidal rule assuming that the trough concentration is equal to the concentration at 12 h. The MPA whole blood concentrations were measured using the EMIT method (Dade Behring). We tested a previously published LSS model including 3-sample times performed at T0, T30 min and T2h (7.75 + 6.49 C0 +0.76 C30min + 2.43 C2h). Results: Trough blood concentrations of Sir at day 15 and months 1, 2 and 3 post-transplant were respectively 15.9±7.7, 14.8±6.2, 16.3±4.9 and 13.2±3.6 ng/ml respectively, and the corresponding mean dose adjusted MPA AUC 0-12 were 72.9±36.7, 78.7±27.0, 82.0±32.6 and 76.4±26.6 ng.h/ml. The correlation between the calculated AUC0-12 using the LSS with three time points and the reference AUC0-12 including all time points showed an excellent correlation at day 15, month 1, 2 and 3 post-transplant (r2 = 0.89, r2= 0.86, r2 = 0.94 and r2 = 0.86 respectively). Conclusion: This study shows that a LSS previously developed in patients treated with concomitant Tacro can be applied in patients receiving Sir and provides an effective method for the estimation of MPA AUC.