MPA-AUC Targets in Childhood INS with Rituximab

Introduction Mycophenolic acid (MPA) is a commonly used steroid-sparing immunosuppressant in nephrotic syndrome. Therapeutic drug monitoring (TDM) based on area under the concentration-time curve (AUC) target ranges is not well established. We aimed to propose exposure TDM targets for MPA in children with nephrotic syndrome when used concomitantly with rituximab. Methods We performed a retrospective analysis of children with nephrotic syndrome treated with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium. Exposures included MPA-AUC 0-12h , MPA trough concentrations, and MMF equivalent dose. Clinical outcomes included relapse rate, time-to-relapse and adverse effects. We determined a favorable MPA-AUC 0-12h range, based on time-to-relapse and adverse effects. Poisson regression models with natural splines and receiver operating characteristic curves were used. Results A total of 131 MPA-AUC 0-12h measurements were performed among 67 children with frequent-relapsing nephrotic syndrome. MPA-AUC 0-12h , but not trough concentration or MMF equivalent dose, was strongly correlated with relapse rate and time-to-relapse. A 10mg*hr/L increase of MPA-AUC 0-12h was associated with fewer relapses (incidence rate ratio [IRR] 0.70, 95%CI 0.59-0.82) and longer time-to-relapse (hazard ratio 0.77, 95%CI 0.64-0.92). For relapse rate, the best model fit was achieved using two knots at MPA-AUC 0-12h of 41 and 57mg*hr/L. Higher MPA-AUC 0-12h , especially ≥ 60mg*hr/L, was associated with increased risk of neutropenia (odds ratio 1.18 per 10mg*hr/L increase, 95%CI 1.02-1.36). Conclusions Our findings suggest an initial target MPA-AUC 0-12h between 40-60mg*h/L provided a favorable balance between relapse prevention and adverse effects. Further increases of MPA-AUC 0-12h above 60mg*h/L may provide further relapse risk reduction, but should be carefully weighed against neutropenia risk.