Using real-world data to inform dosing strategies of rituximab for pediatric patients with frequent-relapsing or steroid-dependent nephrotic syndrome: a prospective pharmacokinetic-pharmacodynamic study.

Rituximab is frequently used off-label for the treatment of frequent-relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a two-compartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19 lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during follow-up at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19 lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. In total, 102 measurements of CD19 lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19 lymphocyte counts, where the E and EC were estimated to be 99.6*10/L and 5.87 μg/mL, respectively. Simulations indicated that a single infusion of 750 mg/m and 2 infusions of 375 mg/m both yielded a 10-week suppression of CD19 lymphocytes. This study represents a first attempt to quantitatively describe the PK-PD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes.