A Systematic Review of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid Area Under the Concentration-Time Curve Estimation

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 MPA LSSs: 2.8401 + 5.7435 x C0 + 0.2655 x C0.5 + 1.1546 x C1 + 2.8971 x C4 for adult renal transplant recipients, 1.783 + 1.248 x C1 + 0.888 x C2 + 8.027 x C4 for adults after islet transplantation, 0.10 + 11.15 x C0 + 0.42 x C1 + 2.80 x C2 for adults after heart transplantation, and 8.217 + 3.163 x C0 + 0.994 x C1 + 1.334 x C2 + 4.183 x C4 for pediatric renal transplant recipients, plus one fMPA LSS, 34.2 + 1.12 x C1 + 1.29 x C2 + 2.28 x C4 + 3.95 x C6 for adult liver transplant recipients, seemed to be the most promising and should be validated in independent patient groups before introduction into clinical practice. The LSSs for pediatric patients were few and not fully characterized. There were only a few fMPA LSSs although fMPA is a pharmacologically active form of the drug. Conclusions The review includes updated MPA LSSs, e.g., for different MPA formulations (suspension, dispersible tablets), generic form, and intravenous administration for adult and pediatric patients, and emphasizes the need of individual therapeutic approaches according to MMF indication. Five MLR-based MPA LSSs might be implemented into clinical practice after evaluation in independent groups of patients. Further studies are required, e.g., to establish fMPA LSS in pediatric patients.