Limited sampling strategy to predict mycophenolic acid area under the curve in pediatric patients with nephrotic syndrome: a retrospective cohort study

Abstract

Purpose Limited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches. Methods We measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0-12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively. Results The best three time point equations included C 1 , C 3 , C 6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85-0.46); C 1 , C 2 , C 6 (good guess 72%, bias 0.72%; 95% CI − 5.33-7.69); and C 1 , C 2 , C 4 (good guess 72%, bias 2.05%; 95% CI − 4.92-13.01) for STATISTICA software. For R software, the best equations consisted of C 1 , C 3 , C 6 (good guess 92%, bias − 2.69%; 95% CI − 27.18-33.75); C 0 , C 1 , C 3 (good guess 84%, bias − 2.11%; 95% CI − 24.19-22.29); and C 0 , C 1 , C 2 (good guess 84%, bias − 0.48%; 95% CI − 30.77-54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method. Conclusions The most useful equations included C 0 , C 1 , C 3 and C 0 , C 1 , C 2 time points; however, the most precise included C 1 , C 3 , C 6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

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

“…Estimating LSS is the approach of TDM applied for many drugs, e.g., MPA, levofloxacin, and etoposide [ 49 , 50 , 51 ]. We recently established and compared LSS for MPA in children with nephrotic syndrome using two different approaches [ 52 ]. In the present study, we used the MPA LSSs found in the literature in the attempt to assess their practicability for the estimation of MPA exposure and to find the optimal time points for MPA TDM in children with nephrotic syndrome.…”

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

“…The search of the literature returned 55 studies concerning MLR LSSs for MPA and fMPA. In this review, 126 MLRbased LSS formulae were included [16][17][18][19][20], among which two studies included both MPA and fMPA LSS [40,61] and one study concerned only fMPA LSS [51]. There was one study which considered patients receiving either MMF or EC-MPS as one group and established the MPA LSSs for them [30].…”

“…A total of 25 LSSs established for pediatric patients were included. These LSSs were found in 11 studies [16][17][18][19][63][64][65][66][67][68][69]. Most of these concerned children after renal transplantation [16,17,65,66,68,69].…”

“…Each MLR LSS constitutes an equation: [14]. Such strategies have been proposed for MPA in many groups of patients [15][16][17][18][19], with emphasis that each LSS should be applied to the same group of patients for whom it was established [20]. As it does not depend on the pharmacokinetic model of the drug and can be calculated with simple software or manually [14], MLR is easier to use in clinical practice than Bayesian analysis; however, the MLR approach has some limitations.…”

“…Each MLR LSS constitutes an equation: AUC = b + M t 1 × C t 1 + M t 2 × C t 2 + M t 3 × C t 3 + … + M ti × C ti , where AUC indicates predicted AUC, b indicates the intercept, C t 1 , C t 2 , C t 3 , C ti indicate the concentrations obtained at t 1 t 2 , t 3 and t I time points, respectively, and M t 1 , M t 2 , M t 3 and M ti indicate the coefficients associated with each timed concentration [ 14 ]. Such strategies have been proposed for MPA in many groups of patients [ 15 – 19 ], with emphasis that each LSS should be applied to the same group of patients for whom it was established [ 20 ]. As it does not depend on the pharmacokinetic model of the drug and can be calculated with simple software or manually [ 14 ], MLR is easier to use in clinical practice than Bayesian analysis; however, the MLR approach has some limitations.…”