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

Abstract

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.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study

“…For adult HSCT patients, the recommended MMF dosage is determined to be administered at 10–15 mg/kg twice daily or 1 g twice daily [ 12 , 13 ]. Although dosing regimens for pediatric HSCT patients have been extrapolated from pediatric solid organ transplantation and adult HSCT pharmacokinetic studies [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ], there is no standardized dosing regimen for pediatric HSCT recipients due to a lack of clinical evidence. The MMF label suggests dosage based on body surface area (BSA) (600 mg/m 2 ) in pediatric solid organ transplant recipients, but in HSCT recipients, dosages vary between BSA-based dosing and weight (kg)-based dosing [ 9 , 10 , 11 , 30 ].…”

“…This target AUC 0–12 within the range of 30–60 mg·h/L also has been reported to reduce the incidence of acute and chronic GVHD [ 11 , 35 , 36 ]. Numerous population pharmacokinetics (PPK) studies have investigated MMF in pediatric solid organ transplantation [ 14 , 15 , 16 , 18 , 20 , 21 , 28 ]. In those studies, age, body weight, BSA, time since transplantation, and renal function were identified as notable influencing factors for inter-individual PK difference [ 14 , 15 , 16 , 18 , 20 , 21 , 28 ].…”

“…Numerous population pharmacokinetics (PPK) studies have investigated MMF in pediatric solid organ transplantation [ 14 , 15 , 16 , 18 , 20 , 21 , 28 ]. In those studies, age, body weight, BSA, time since transplantation, and renal function were identified as notable influencing factors for inter-individual PK difference [ 14 , 15 , 16 , 18 , 20 , 21 , 28 ]. However, there is a noticeable lack of PPK-based evidence for pediatric HSCT recipients.…”