Evaluation of Limited Sampling Strategies for Mycophenolic Acid After Mycophenolate Mofetil Intake in Adult Kidney Transplant Recipients

Abstract

Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular relevance when choosing a LSS.

Limited-Sampling Strategy for Mycophenolic Acid in Renal Transplant Recipients Reciving Enteric-Coated Mycophenolate Sodium and Tacrolimus

“…Not achieving an adequate AUC 0-12h may have important implications for therapeutic efficacy 12 ; consequently, LSS are recommended because MPA predose concentrations are only weakly correlated with AUC 0-12h . [18][19][20][21][22][23] Limited sampling for 2-3 hours after MMF can lead to an acceptable estimation of MPA AUC 0-12h , and different algorithms have been published. [18][19][20][21][22][23] However, these LSS cannot be used for EC-MPS, because delivery of MPA with this formulation in the intestine is more variable than delivery of MMF.…”

“…Substantial research has been conducted to develop LSS to estimate MPA AUC 0-12h in solid organ recipients treated with MMF. [19][20][21][22] However, evidence in patients treated with EC-MPS is scant.…”

Simulation Based Assessment of Limited Sampling Strategies Reliability in the Estimation of the Area Under the Concentration-Time Curve

“…However, the limitation of these methods is that they are based on data collected bearing similar conditions. The generalizability and transferability of these developed LSS to another setting remains an open problem [9,16,18]. This is what we addressed in the current paper.…”

“…The predictive performance of LSS is generally evaluated through the calculation of their bias and precision [17]. Though these criteria inform a certain validity of the LSS, their predictive power and transferability should not be taken for granted when different patient subpopulations and contexts are involved [18]. This fact explains the variety of LSS reported for the same drug by different research groups [9,19].…”

Mycophenolic acid agents: is enteric coating the answer?

“…Alternatively, limited sampling strategies, where MPA exposure is estimated from a few samples, have shown good correlation with AUC 0-12h . 44,45 Recently, prospective, randomized, multicenter studies validating the benefit of TDM using LSS have been published. 35,36 The APOMYGERE trial, applying the population-based pharmacokinetic model and maximum a posteriori probability Bayesian methodology, found that the incidence of treatment failure was significantly lower in the concentration-controlled group.…”