Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus

Abstract

Introduction: Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC_{0-12 h} using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance.

Methods: Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC_{0-12 h} at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults.

Results: We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC_{0-12 h}. The external validation MPA AUC_{0-12 h} was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively.

Conclusion: According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC_{0-12 h} in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC_{0-12 h} between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.

Keywords: Bayesian estimator; Juvenile lupus erythematosus; Mycophenolate mofetil; Pediatrics; Pharmacokinetics.