Pharmacokinetics of Mycophenolate Mofetil and Development of Limited Sampling Strategy in Early Kidney Transplant Recipients

Abstract

The mycophenolate mofetil (MMF) dose management for optimization of post-transplant treatment especially the early postoperative phase has been well recognized. MMF is a pro-drug of mycophenolic acid (MPA) and is widely used in Chinese renal transplant patients. Until now, the pharmacokinetic (PK) characteristics and model for the area under the concentration–time curve for the 12-h (h) of exposure (AUC0-12 h) of MPA (MPA-AUC0-12 h) estimation were lacking for the new formulation of MMF dispersible tablet in renal transplant patients. The aims of the study were to investigate the PK characteristics of MMF dispersible tablet by detecting the active metabolite of MPA and to establish an accuracy and precision equation for calculating MPA-AUC0-12 h by limited sampling strategy (LSS) in Chinese kidney transplant patients. A total of 60 postoperative kidney transplant recipients were given a multiple-dose of MMF dispersible tablet twice daily combination with tacrolimus (Tac) and steroids. On the 5th day post-transplantation, blood specimens were collected before drug administration and up to 12 h after MMF dispersible tablet administration. Non-compartmental PK analysis was used to determine the data obtained from individual patients. Multivariate stepwise regression analysis was used to develop models for predicting MPA-AUC0-12 h. The 3- and 4-point sampling models using 2 h, 4 h, 8 h and 1 h, 2 h, 4 h and 8 h, respectively, allowed accurate estimation of MPA-AUC0-12 h. PK parameters of MMF dispersible tablet were obtained and the 4-point LSS is the best model for accurate and precise estimation of MPA-AUC0-12 h.

Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients

“…Therefore, the three time-point (C1, C4, and C8) equations were developed (MPA AUC0-12 = 4.04 + 1.64•C1 + 3.08•C4 + 5.17•C8, r = 0.923, P < 0.001, AcMPAG AUC0-12 = -0.13 + 3.01•C1 + 3.51•C4 + 5.74•C8, r = 0.955, P < 0.001). Compared to previous reports (30,31), the three time-point equations developed in this study have a relatively better predictive performance (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). Moreover, about 80% of the estimated AUC was within ± 15% of the observed AUC.…”

Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

“…The BA analysis was expressed by the scatter diagram and limits of agreement. The lower limit of 95% CI < 0.9 and the limits of agreement within ±15% were acceptable for the clinic (Zhang et al, 2018). The best model was selected based on the values of r 2 , PE, RMSE, ICC, and BA analysis.…”

“…To solve this problem, the limited sampling strategy (LSS), estimating AUC with one or a few samples, would be suitable in the clinic (David and Johnston, 2000). It has been proposed for TDM of many drugs, such as mycophenolate mofetil and colistin (Zhang et al, 2018;Kim et al, 2019;Van Der Galiën et al, 2020). However, no LSS report is available for polymyxin B at present.…”

Mycophenolic acid pharmacogenomics in kidney transplantation

“…The strategies applied to MPA dosing were different between studies, which included fixed dosing ("onedose-fits-all") and dosing to a therapeutic range (therapeutic drug monitoring-TDM). MPA AUC 0-12 has been recommended as the best marker for dose adjustment [87] . However, unlike other drugs such as tacrolimus, MPA trough level showed a poor correlation with AUC [87][88][89] .…”

“…MPA AUC 0-12 has been recommended as the best marker for dose adjustment [87] . However, unlike other drugs such as tacrolimus, MPA trough level showed a poor correlation with AUC [87][88][89] . TDM use for MPA is drawing much attention, but it is still controversial [3] .…”