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Background and Objective One approach of therapeutic drug monitoring in the case of mycophenolic acid (MPA) is a limited sampling strategy (LSS), which allows the evaluation of the area under the concentration-time curve (AUC) based on few concentrations. The aim of this systematic review was to review the MPA LSSs and define the most frequent time points for MPA determination in patients with different indications for mycophenolate mofetil (MMF) administration. Methods The literature was comprehensively searched in July 2021 using PubMed, Scopus, and Medline databases. Original articles determining multiple linear regression (MLR)-based LSSs for MPA and its free form (fMPA) were included. Studies on enteric-coated mycophenolic sodium, previously established LSS, Bayesian estimator, and different than twice a day dosing were excluded. Data were analyzed separately for (1) adult renal transplant recipients, (2) adults with other than renal transplantation indication, and (3) for pediatric patients. Results A total of 27, 17, and 11 studies were found for groups 1, 2, and 3, respectively, and 126 MLR-based LSS formulae (n = 120 for MPA, n = 6 for fMPA) were included in the review. Three time-point equations were the most frequent. Four

LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.

Purpose Limited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches. Methods We measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0-12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively. Results The best three time point equations included C 1 , C 3 , C 6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85-0.46); C 1 , C 2 , C 6 (good guess 72%, bias 0.72%; 95% CI − 5.33-7.69); and C 1 , C 2 , C 4 (good guess 72%, bias 2.05%; 95% CI − 4.92-13.01) for STATISTICA software. For R software, the best equations consisted of C 1 , C 3 , C 6 (good guess 92%, bias − 2.69%; 95% CI − 27.18-33.75); C 0 , C 1 , C 3 (good guess 84%, bias − 2.11%; 95% CI − 24.19-22.29); and C 0 , C 1 , C 2 (good guess 84%, bias − 0.48%; 95% CI − 30.77-54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method. Conclusions The most useful equations included C 0 , C 1 , C 3 and C 0 , C 1 , C 2 time points; however, the most precise included C 1 , C 3 , C 6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.