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

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.

Effect of Meal Timings and Meal Content on the AUC0‐12h of Mycophenolic Acid: A Simulation Study

“…As shown in Figure S3, for most LSS equations established with a specified postdose fasting period, a good prediction of steady-state AUC 0-12h can be provided within ±0.5 hour around that postdose fasting period. The 0.5-hour tolerance range for the postdose fasting period can also be observed from the results of LSSs evaluated by Sobiak et al 21 Where 3 studies by Filler et al had satisfactory predictive performance, and the postdose fasting period was 0.5 hours earlier than in the trial by Sobiak et al [53][54][55] Nevertheless, limited studies have reported meal information, and the current data from clinical studies are insufficient for validating or evaluating the relationship between the postdose fasting period and LSS performance. Worldwide data are required to evaluate the changes in mycophenolic acid exposure under various meal scenarios.…”

“…Although LSS has good predictive performance in internal validations, several cross-center evaluations suggested that most mycophenolic acid LSS equations from other centers yielded bias when predicting the AUC 0-12h. [18][19][20][21] The biased estimates of mycophenolic acid AUC 0-12h may be related to the EHC process. 22,23 Therefore, understanding the EHC process and its associated variability is vital to accurately predict the AUC 0-12h of mycophenolic acid and thus perform a valid TDM.…”

Two Innovative Approaches to Optimize Vancomycin Dosing Using Estimated AUC after First Dose: Validation Using Data Generated from Population PK Model Coupled with Monte-Carlo Simulation and Comparison with the First-Order PK Equation Approach

“…However, our approaches are worth considering, as the potential benefits outweigh the costs and efforts. Medications such as Busulfan and Mycophenolic acid have similar issues, but are monitored well in clinic with 2–6 samples (Busulfan) or limited sampling strategy with 3 samples (Mycophenolic acid) [ 63 , 64 ]. Close cooperation between clinicians and nurses is critical for efficient achievement of TDM for highly potent and sensitive drugs.…”

Sustained suppression of enterohepatic circulation of mycophenolic acid by antimicrobial‐associated diarrhea in a kidney transplant recipient with Crohn's disease: A case report

“… 14 Hence, AUC 0–12 calculated by multiple blood sampling or limited sampling strategy is recommended as an index that reflects MPA exposure in the body. 15 , 16 , 17 , 18 , 19 Trough level, meanwhile, is used as an alternative indicator when multiple blood sampling is not possible. A previous report indicated that concomitant use of oral antibiotics with MMF reduced MPA trough level by approximately 50%, while AUC 0–12 of MPA decreased by only 10%–30%.…”

“…The trough concentration is highly affected by this second peak and therefore has a low correlation with the area under the curve (AUC 0–12 ) 14 . Hence, AUC 0–12 calculated by multiple blood sampling or limited sampling strategy is recommended as an index that reflects MPA exposure in the body 15–19 …”