Limited Sampling Strategy for Estimating Area under the Concentration Curve for Mycophenolic Acid in Renal Transplant Recipients with Co-administration of Tacrolimus

Abstract

To obtain an adequate immunosuppressive effect of mycophenolate mofetil (MMF), various equations have been used for estimating the area under the concentration curve (AUC) for mycophenolic acid (MPA) under a limited sampling strategy. Most of them, however, involved cyclosporine (CYA) -based immunosuppression. In this study, we measured chronological blood concentrations of MPA when included in tacrolimus (TAC, alternative calcineurin inhibitor) -based triple-drug immunosuppression in renal transplant recipients and investigated the effectiveness of a limited sampling strategy which minimized patients' inconvenience.
Measurement of MPA concentrations in consecutive samplings over a 24-hour period in 6 renal transplant recipients receiving TAC-based triple-drug immunosuppression therapy (MMF dose : 1250-2000 mg/day, twice a day), showed substantial inter-patient and intra-patient variability in MPA pharmacokinetics. The second MPA peak was observed in 8 concentration profiles. There were no significant differences in T_max, T_lag, dose-normalized C_max, pre-dose concentration (C₀), and AUC (0-12) (AUC (τ)) between morning and evening dosing.
Regarding a relationship between AUC (τ) and the MPA concentrations for each sampling point, despite the substantial variation in MPA pharmacokinetics, a significant correlation was found between C₀ and AUC (τ) (r²= 0.734). The highest r² value was obtained at C₈ (r²=0.852). The optimum combination of sampling time points for estimating AUC for MPA using stepwise linear regression was C₀, C₃, C₈ (r²= 0.964) and this combination had the lowest maximum prediction error (22.6%) in the estimation of AUC (τ). From the above findings, we recommend the use of the formula AUC (τ) (μg·h/ mL) = 7.82 +3.58· C₀ + 1.87· C₃ + 7.15 ·C₈ for estimating the AUC for MPA in renal transplant recipients also receiving TAC.