P74 Rituximab effect on B cell depletion in paediatric patients with autoimmune diseases: a retrospective dose-response analysis of an observational study

Background Rituximab is a chimeric IgG1 monoclonal antibody that depletes B cells for the treatment of several conditions including autoimmune diseases. It is not licensed for use in children but administered off-label. This study aimed to quantify the effect of rituximab on B cell depletion in children with autoimmune diseases and to optimise the dosing regimen. Methods Electronic health record data were collected from a retrospective and anonymised study at Great Ormond Street Hospital in London. Dosing protocols of rituximab were two 750 mg/m2 intravenous infusions or four weekly 375 mg/m2 infusions. Serum concentrations of rituximab were not measured. CD19+ lymphocyte counts were taken before and after rituximab treatment. A turnover mechanism described the life cycle of CD19+ lymphocytes with rituximab increasing the death rate of CD19+ lymphocytes; a negative feedback was added on the production rate to examine the rebound effect. Rituximab was assumed to decay by first-order kinetics. Results 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The dose-response model well described the time course of CD19+ lymphocytes following rituximab administration. The elimination half-lives of rituximab and CD19+ lymphocytes were estimated to be 19 and 35 days, respectively, consistent with findings from other studies [1–5]. The rebound increase in CD19+ lymphocytes was found negligible. Methotrexate and cyclophosphamide increased the maximum death rate by 66% and 38% respectively. Age and gender were not significant covariates. Simulations from the model suggested that a single infusion of rituximab of 375 mg/m2 can provide similar six-month suppression of CD19+ lymphocytes to the higher doses currently used. Methotrexate or cyclophosphamide added minimal suppression effect on CD19+ lymphocytes when taken concurrently with rituximab. Conclusions Our results could be used in future to assess the effect of rituximab biosimilars and to inform biosimilar dosing in paediatric populations. References Ng, et al. J Clin Pharmacol. 2005; 45:792–801 Li, et al. Blood. 2007; 110:2371 Li, et al. J Clin Pharmacol. 2012; 52:1918–26 Fulcher and Basten. Immunol Cell Biol. 1997; 75:446–55 Macallan, et al. Blood. 2005; 105:3633–40 Disclosure(s) Nothing to disclose