Therapeutic drug monitoring of mycophenolate mofetil in pediatric patients: novel techniques and current opinion

Ehren, Rasmus; Schijvens, Anne M; Hackl, Ágnes; Schreuder, Michiel F.; Weber, Lutz T.

doi:10.1080/17425255.2021.1843633

Cited by 18 publications

(36 citation statements)

References 111 publications

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“…Determination of plasma fMPA concentration may be helpful in special situations such as the occurrence of MPA-related toxicity even if tMPA is within the therapeutic window. 33 The pharmacokinetics of tMPA and fMPA are known to exhibit considerable variability between individuals and some variability across age groups. 20,21 In this study, the pharmacokinetic profiles of tMPA and fMPA in adult and paediatric renal transplant recipients after MMF administration were compared.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibition of IMPDH depends on the fMPA exposure. Determination of plasma fMPA concentration may be helpful in special situations such as the occurrence of MPA‐related toxicity even if tMPA is within the therapeutic window 33 . The pharmacokinetics of tMPA and fMPA are known to exhibit considerable variability between individuals and some variability across age groups 20,21 .…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants

Liu

Zhang

et al. 2022

Basic Clin Pharma Tox

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Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and genetic factors could explain the variability in the pharmacokinetics of free MPA (fMPA) and total MPA (tMPA) in Chinese paediatric and adult renal transplant recipients. Twenty-eight paediatric and 31 adult patients were enrolled, and the concentrations of tMPA and fMPA were determined at 0 h (predose) and 0.5, 1, 1.5, 2, 4, 5, 8, 9, 10 and 12 h after mycophenolate mofetil administration. Genetic polymorphisms of UGTs (rs671448, rs1042597, rs2741049, rs62298861, rs7439366, rs12233719) and ABCC2 (rs717620) were simultaneously determined. The clinical and genetic data were analysed and reported. tMPA and fMPA concentrations adjusted for dose per body weight were consistently higher in adults than in paediatric patients. In the paediatric group, only albumin and time after transplantation correlated significantly with the MPA-free fraction variation, which could explain 32.4% of the variability. Besides, ABCC2 polymorphism, albumin and time after transplantation correlated significantly with the MPA-free fraction variation in adults, which could explain 56.9% of the variability. The influencing factors in the paediatric group are different from those in adults, which may be due to age-related transporter expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants

Liu

Zhang

et al. 2022

Basic Clin Pharma Tox

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“…Among all MPA LSSs included in this review, the most often used time points were 2 h after MMF administration, that is near MPA t max [ 1 ], and 6 h after MMF administration. Surprisingly, in adult renal transplant recipients, the most often used time point was C4, which is between t max and t max2 [ 82 ]. C0 was the most frequently included only in LSSs for pediatric patients.…”

Section: Discussionmentioning

confidence: 99%

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

Sobiak

Resztak

2021

Eur J Drug Metab Pharmacokinet

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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

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“…MMF is a prodrug that undergoes rapid hydrolyzation to the active metabolite mycophenolic acid (MPA) following oral administration [ 6 , 7 ]. The major MPA is further transformed to the 7- O -mycophenolic acid glucuronide (MPAG), which is inactive but exhibits enterohepatic recirculation (EHC) that can cause the double absorption pharmacokinetic (PK) process [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…The minor part of MPA is later metabolized to acyl-glucuronide (AcMPAG) [ 9 ]. MPA selectively and reversibly inhibits an enzyme called inosine monophosphate dehydrogenase (IMPDH), which plays a key role in the de novo purine biosynthesis [ 7 , 10 ]. By blocking the pathway above, MPA inhibits T and B lymphocytes from proliferating, thus causing immunosuppression to prevent graft rejection [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area

Wang

Huang

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods. Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30–60 mg·h/L). Results. A total of 96 pediatric patients aged at 13.3 (range 4.3–18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6–18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22–0.46 m2, 180 mg every 24 hours with BSA of 0.47–0.67 m2, 180 mg every 24 hours with BSA of 0.68–0.96 m2, 360 mg every 24 hours with BSA of 0.97–1.18 m2, 540 mg every 24 hours with BSA of 1.19–1.58 m2, and 360 mg every 12 hours with BSA of 1.59–2.03 m2. Conclusion. BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m 2 is warranted.

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Therapeutic drug monitoring of mycophenolate mofetil in pediatric patients: novel techniques and current opinion

Cited by 18 publications

References 111 publications

Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants

Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants

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

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area

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