Generation and Validation of a Limited Sampling Strategy to Monitor Mycophenolic Acid Exposure in Children With Nephrotic Syndrome

Abstract

Background: Mycophenolate mofetil (MMF) plays an increasingly important role in the treatment of children with nephrotic syndrome, especially in steroid sparing protocols. Recent publications show the relationship of exposure to its active moiety mycophenolic acid (MPA) and clinical efficacy. Performance of full-time pharmacokinetic (PK) profiles, however, is inconvenient and laborious. Established limited sampling strategies (LSS) to estimate the area under the concentration (AUC) versus time curve of MPA (MPA-AUC) in pediatric renal transplant recipients cannot be easily transferred to children suffering from nephrotic syndrome, mainly because of the lack of concomitant immunosuppressive therapy. We therefore aimed for the generation and validation of a LSS to estimate MPA exposure to facilitate therapeutic drug monitoring in children with nephrotic syndrome. Methods: We performed 27 complete PK profiles in 23 children in remission [mean age (±SD):12.3 ± 4.26 years] to generate and validate an LSS. Sampling time points were before administration (C0) and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours after the administration of MMF. MPA was measured by enzyme multiplied immunoassay technique. There was no concomitant treatment with calcineurin inhibitors. Results: Mean daily dose of MMF was 927 ± 209 mg/m2 of body surface area resulting in a mean MPA-AUC0-12 value of 59.2 ± 29.3 mg × h/L and a predose level of 3.03 ± 2.24 mg/L. Between-patient variability of dose-normalized MPA-AUC0-12 was high (coefficient of variation: 45.5%). Correlation of predose levels with the corresponding MPA-AUC0-12 was moderate (r 2 = 0.59) in a subgroup of 18 patients (20 PK profiles, generation group). An algorithm based on 3 PK sampling time points during the first 2 hours after MMF dosing (estimated AUC0-12 = 8.7 + 4.63 × C0 + 1.90 × C1 + 1.52 × C2) was able to predict MPA-AUC with a low percentage prediction error (3.88%) and a good correlation of determination (r 2 = 0.90). Validation of this algorithm in a randomized separate group of 6 patients (7 PK profiles, validation group) resulted in comparably good correlation (r 2 = 0.95) and low percentage prediction error (5.57%). Conclusions: An abbreviated profile within the first 2 hours after MMF dosing gives a good estimate of MPA exposure in children with nephrotic syndrome and hence has the potential to optimize MMF therapy.

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

“…The search of the literature returned 29 studies meeting the requirements concerning MLR LSSs for MPA and fMPA, dated 1998–2020. We applied 48 MPA LSSs [ 8 , 9 , 14 , 21 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] and five fMPA LSSs [ 35 , 36 , 42 ] found in the literature to calculate the predicted area under the (0–12 h) time–concentration curve (AUC pred ) in children with nephrotic syndrome treated with MMF, and compared the results with AUC total . In the majority of studies, calcineurin inhibitors (CsA or tacrolimus (Tac)) were co-administered with MMF.…”

“…Two of nine the best LSSs included liver transplant recipients [ 28 , 29 ]. Surprisingly, the LSSs established for children with nephrotic syndrome [ 14 , 25 ] or lupus erythematosus [ 21 ] performed poorly as they did not fulfill the criteria: the values of r 2 were below 0.800, and ≤50% of the AUC pred values were within ±15% of the AUC total . These poor results may be explained by one time point equation in the Hibino et al study [ 14 ] and the relatively high intercept.…”

“…This evidence suggests that the MPA C max and C max2 influence its AUC the most, and the blood samples should be collected at least in three time points near C max and C max2 to precisely predict the AUC. According to the literature, for children with nephrotic syndrome C 2 or time points up to 2 h after MMF administration should be included in the MPA LSS [ 14 , 25 ]. The inclusion of C 6 makes using LSS cumbersome.…”

“…CsA inhibits MPA enterohepatic recirculation, causing a decrease in MPA exposition, and therefore blood sampling does not require including time-points around the MPA C max2 when MMF is co-administered with CsA [ 16 ]. Among the LSSs applied in this study, only in three studies with MLR LSSs [ 21 , 25 , 46 ] did the patients not receive concomitant medications (in one study only 8% of patients received CsA [ 46 ]). Surprisingly, in our study, for these LSSs the predictive performance fell beyond ±15% range.…”

Quantification of mycophenolic acid in human plasma by liquid chromatography with time‐of‐flight mass spectrometry for therapeutic drug monitoring

“…Mycophenolic acid (MPA)/mycophenolate (Figure 1) is one of the most frequently prescribed immunosuppressant drugs to prevent organ rejection in solid organ transplantation, particularly in renal, liver and lung transplantation (Kaufman et al, 2004; Staatz & Tett, 2007). Furthermore, MPA is used in the treatment of nephrotic syndrome in children (Benz et al, 2019), lupus nephritis (Ranganathan et al, 2019) and systemic lupus erythematosus, as well as in other autoimmune diseases such as psoriasis and Crohn’s disease (Strathie Page & Tait, 2015).…”