Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients

Abstract

To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.