The Evaluation of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid in Children with Nephrotic Syndrome.

Joanna Sobiak,Jacek Zachwieja,Matylda Resztak,Maria Chrzanowska,Danuta Ostalska-Nowicka

doi:10.3390/molecules26123723

Joanna Sobiak, Jacek Zachwieja + Show 3 more

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https://doi.org/10.3390/molecules26123723

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Abstract

We evaluated mycophenolic acid (MPA) limited sampling strategies (LSSs) established using multiple linear regression (MLR) in children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MLR-LSS is an easy-to-determine approach of therapeutic drug monitoring (TDM). We assessed the practicability of different LSSs for the estimation of MPA exposure as well as the optimal time points for MPA TDM. The literature search returned 29 studies dated 1998–2020. We applied 53 LSSs (n = 48 for MPA, n = 5 for free MPA [fMPA]) to predict the area under the time-concentration curve (AUCpred) in 24 children with nephrotic syndrome, for whom we previously determined MPA and fMPA concentrations, and compare the results with the determined AUC (AUCtotal). Nine equations met the requirements for bias and precision ±15%. The MPA AUC in children with nephrotic syndrome was predicted the best by four time-point LSSs developed for renal transplant recipients. Out of five LSSs evaluated for fMPA, none fulfilled the ±15% criteria for bias and precision probably due to very high percentage of bound MPA (99.64%). MPA LSS for children with nephrotic syndrome should include blood samples collected 1 h, 2 h and near the second MPA maximum concentration. MPA concentrations determined with the high performance liquid chromatography after multiplying by 1.175 may be used in LSSs based on MPA concentrations determined with the immunoassay technique. MPA LSS may facilitate TDM in the case of MMF, however, more studies on fMPA LSS are required for children with nephrotic syndrome.

Highlights

Mycophenolate mofetil (MMF) is an immunosuppressive drug administered in the prophylaxis against acute rejection after solid organ transplantation as well as in autoimmune diseases [1], nephrotic syndrome [2,3], and atopic dermatitis [4]
mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients are widely described in the literature [1,6,7,8,9,10], the pharmacokinetics are assumed to be different, there are few studies concerning children with nephrotic syndrome treated with MMF [11,12,13,14]
Due to the small number of studies on MPA pharmacokinetics in children with nephrotic syndrome, in this study we evaluated multiple linear regression (MLR)-based limited sampling strategies (LSSs) found in the literature in children with nephrotic syndrome treated with MMF

Summary

Introduction

Mycophenolate mofetil (MMF) is an immunosuppressive drug administered in the prophylaxis against acute rejection after solid organ transplantation as well as in autoimmune diseases [1], nephrotic syndrome [2,3], and atopic dermatitis [4]. MPA pharmacokinetics in renal transplant recipients are widely described in the literature [1,6,7,8,9,10], the pharmacokinetics are assumed to be different, there are few studies concerning children with nephrotic syndrome treated with MMF [11,12,13,14]. In our previous study [11], we observed that the target values of the pharmacokinetic parameters, such as the concentration before the dose (C0) and the area under the concentration—time curve from 0 to 12 h (AUCtotal), in children with nephrotic syndrome treated with MMF should be higher than those recommended after renal transplantation [1]. Tong et al [23] applied the LSS established with the high performance liquid chromatography (HPLC) method to evaluate the AUC for patients for whom the enzyme multiplied immunoassay technique (EMIT) was used for MPA determination, while Neuberger et al [24] applied an MPA LSS established after the administration of another MPA formulation, enteric-coated mycophenolic sodium (ECMPS), in MMF treated patients

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